1

This is the pre-peer reviewed version of the following article: A Stereodivergent Strategy for the Preparation of Corynantheine and Ipecac Alkaloids, there Epimers and Analogs: Efficient Total Synthesis of (-)-Dihydrocorynantheol, (-)-Corynantheol, (-)-Protoemetinol, (-)-Corynantheal, (-)-Protoemetine and Related Natural and Non-Natural Compounds. Zhang, W.; Bah, J.; Wohlfarth, A.; Franzén, J. Chem.-Eur. J. 2011 17, 13814, which has been published in final form at: http://onlinelibrary.wiley.com/doi/10.1002/chem.201102012/abstract

A Stereodivergent Strategy for the Preparation of Corynantheine and Ipecac Alkaloids, there Epimers and Analogs: Efficient Total Synthesis of (-)-

Dihydrocorynantheol, (-)-Corynantheol, (-)-Protoemetinol, (-)-Corynantheal, (-)-Protoemetine and Related Natural and Non-Natural Compounds.

Wei Zhang, [a] Juho Bah, [a] Andreas Wohlfarth[a] and Johan Franzén*[a]

Dedication ((optional))

Abstract: Here is presented a general and common catalytic asymmetric strategy for the total and formal synthesis of a broad number of optically active natural products from the Corynantheine and Ipecac alkaloid families e.g. Indolo[2,3-a]- and Benzo[a]quinolizidines. Construction of the core alkaloid skeletons, with the correct absolute and relative stereochemistry, relays on an enantioselective and diastereodivergent one-pot cascade sequence followed by an additional diastereodivergent reaction step. This allows for enantio-

and diastereoselective synthesis of three out of four possible epimers of the quinolizidine alkaloids starting from common and easily accessible starting materials using a common synthetic route. Focus has been made on excluding protecting groups and limiting isolation and purification of synthetic intermediates. This methodology is applied in the total synthesis of the natural products (-)-Dihydrocorynantheol, (-)-Hirsutinol, (-)-Corynantheol, (-)-Protometinol, (-)-Dihydrocorynantheal, (-)-Corynantheal, (-)-Protoemetine, (-)-(15S)-

Hydroxydihydrocorynantheol and an array of there non-natural epimers. The potential of this strategy is also demonstrated in the synthesis of biologically interesting natural product analogs not accessible through synthetic elaboration of alkaloid precursors available from nature e.g. thieno[3,2-a]quinolizidine derivatives. We also report the formal synthesis of (+)-Dihydrocorynantheine, (-)-Emetine, (-)-Cephaeline, (-)-Tubulosine and (-)-Deoxytubulosine.

Introduction

The Corynantheine and Ipecac alkaloid families contain a vast number of naturally occurring compounds that share a quinolizidine structural motif. They are mainly isolated from the leaves of Uncaria Tomentosa (cat claw) and the root of Cepahaelis ipecacuanha (Rubiaceae) and have a long history of usage as herbal drugs to treat inflammation, rheumatism, gastric ulcers, tumors, dysentery, as birth control and to promote wound healing. Over the years there have been several studies on the pharmacological properties of the individual alkaloids, which have been shown to possess considerably diverse and interesting biological activity (Figure 1). For example: high antiviral activity is observed for the indoquinolizidines of the corynantheine group, Dihydrocorynanthein and Hirsutine, towards influenza virus type A.[1] The corynantheine family also exhibits anti-inflammatory, [2]

antiarthritic, [3] antibacterial,[4] analgesic[5] and antiallergenic[6] activity. Tubulosine, Emetine and Cephaeline, from the Ipecac alkaloid families, are potent inhibitors of protein biosynthesis.[7] Remarkable activities against several cancer cell lines,[8] for example lymphatic leukaemia,[9] HIV reverse transcriptase inhibitory activities[10] antiprotozoic properties[11] as well as antiamoebic activity have also been observed. Emetine also has a history as a therapeutic emetic. In nature, both Corynantheine and Ipecac alkaloids share the same biosynthetic pathway and are formed through the enzymatic condensation of the monoterpene secologanin with tryptamine and dopamine, respectively. [12,13] From a synthetic point of view, construction of the fused ring system with control of the relative and absolute stereochemistry on the quinolizidine core structure represents a significant challenge and considerable research focus has been placed on the there laboratory preparation.

2

N

R

H

H H

MeOOMe

N

HN

RMeO

OH

MeOH

(+)-Hirsutine (R = Et)(+)-Hirsuteine (R = vinyl)

N

MeOOMe

HO

H

N

R

HN

HO

H

(+)-11b-epi-Protoemetinol

(-)-Dihydrocorynantheol (R = Et)(-)-Corynantheol (R = vinyl)

NH

HN

RO

Corynantheine alkaloidsIpecac alkaloids

HN

MeOOMe

O

H

(-)-Protoemetine

H HHHN

MeOOMe

HO

H

(-)-Protoemetinol

HHH

N

HN

HO

H

H

HO

H

(-)-(15S)-Hydroxy-dihydrocorynantheol

HH

HN

HN

RMeO

OH

MeOH H

(-)-Dihydrocorynantheine(R = Et, R'=H)(+)-Corynantheine(R = vinyl, R'=H)(+)-Speciogynine(R = Et, R'=OH)

N

HO

H

H H

HN

(+)-Hirsutinol

(-)-Dihydrocorynantheal (R = Et)(-)-Corynantheal (R = vinyl)

R'

R =

HNOMe

OR'

H

HNH H

N

(-)-Emetine (R'= Me)(-)-Cephaeline (R'= H)

(-)-Tubulosine (R'= OH)(-)-Deoxytubulosine (R'= H)

R'

Figure 1. Examples of alkaloids from the Corynantheine and Ipecac family.

Traditionally, the major part of previously reported strategies for the asymmetric total synthesis of quinolizidine alkaloids require multi-step synthesis relying on starting materials from the chiral pool.[14] These strategies often include several functional group transformations and tedious protection/deprotection steps. As a consequence, the enantioselective total syntheses of Corynantheine and Ipecac alkaloids and analogs thereof are demanding and proceed in low overall yield. Lately, there have been a few scattered reports of efficient synthesis of optically active quinolizidine natural products and different analogs based on asymmetric catalysis.[15-18] In particular can be mentioned the elegant total synthesis of ent-Dihydrocorynantheol by Itoh et al.[17f] The key step in their strategy is based on an enantioselective proline-catalyzed annulation of 3-ethyl-3-buten-2-one to 9-tosyl-3,4-dihydro-â-carboline, providing the target alkaloid in only three additional steps. Although, highly efficient and productive, the majority of the synthetic strategies developed are target specific with respect to the relative configuration of the quinolizidine stereocenters, only allowing for selective formation of one specific epimer of the alkaloid.[19]

Keeping in mind the structural similarity of the quinolizidine alkaloids (Figure 1), we anticipated that an array of naturally occurring quinolizidine alkaloids, their epimers and analogs, including those not accessible through the synthetic elaboration of naturally occurring alkaloids, could be prepared via a single and general synthetic strategy. Our plan was to develop a common synthetic route to a series of functionalized quinolizidine intermediates with skeletal and stereochemical variation. These epimeric structurally different intermediates are to be designed in such a way that they can be rapidly modified, in a few synthetic operations, to the desired alkaloids with correct absolute and relative stereochemistry. We were also determent to put a considerable focus on the over all efficiency of the synthetic strategy through the implementation of asymmetric one-pot and cascade/tandem reactions.[20,21] Such strategies will have the advantage of avoiding traditional stop-and-go synthesis,[22] reducing tedious isolation and purification of synthetic intermediates and resulting in higher

yielding processes that will allow for practical quantitative preparation of the alkaloids.

In order to meet the requirements for efficient and diverse quantitative total synthesis we set the following objectives: 1) Readily available starting materials, not limited by the chiral pool; 2) easily manageable operational protocols on a multi-gram scale; 3) selective access to different diastereoisomers through stereodivergent reaction steps; 4) low number of synthetic operations, isolations and purifications of reaction intermediates; 5) no protection/deprotection of functional groups 6) easy access to no-natural quinolizidine alkaloid analogues.

In here we wish to report an enantioselective and diastereodivergent synthetic strategy for quantitative preparation of a broad variety of alkaloids containing a quinolizidine substructure that we believe fulfills the above-mentioned criteria.

N

HNH

O

OMe

MeO

N

HNH

O

OMe

MeO

Dihydrocorynantheine

Hirsutine

N

NH

H

OO

OH

Thermodynamic

NNH

H

OO

OHH

Kinetic

H

12b-α-H

12b-β-H

Figure 2: Conformations of the epimeric natural products 12b-α-H Dihydrocorynantheine and 12b-β-H Hirsutine.

3

N11b

2 3 45

109

8

7

6

7a1111a

1 N10b

23 4

5

10

9 8

7

6

7a

10a

1

S

N12b

2 3 45

10 9

8

7

6

7a12a

1

HN

11

7b11a

12

13 12 11

14 13 121516

1415

1314

NH

Ar

H H23

NH

Ar

H H23

NH

Ar

H H23

α-trans β-trans β-cis Figure 3. Nomenclature used through this paper (α and β refers to the ring junction configuration, trans and cis refers to the relative relationship between C2 and C3).

Results and Discussion

Retrosynthetic Analysis: The common structural unit for the Corynantheine and Ipecac alkaloids is the quinolizidine ring containing a fused aromatic group and three stereocenters wherein one is a ring junction stereocenter. The ring junction stereocenter has a great impact on the conformation of the alkaloid as can be seen through comparison of the two naturally occurring ring junction epimers, dihydrocorynantheine and hirsutine, where the former is the thermodynamically most stable form and has all groups on the quinolizidine substructure in the equatorial position (Figure 2).[23] Hirsutine on the other hand has the aromatic group in an axial position that forces a V-shaped form. Interestingly, dihydrocorynantheine and hirsutine have been found to have differing biological activities,[24] thus stereoselective formation of different epimers is highly desired. This requires special considerations during synthesis and has been one of the bottlenecks in previously reported total syntheses of quinolizidine alkaloids.[25]

We came to the conclusion that the four different epimers of quinolizidine derivatives A would be prominent precursors for a broad series of Corynantheine and Ipecac alkaloids, their epimers and different analogs (Scheme 1, Figure 3). The strategy should be based on asymmetric catalysis and we also envisioned a stereodivergent introduction of the following stereocenters by taking advantage of thermodynamic and kinetic reaction conditions. This will allow for fast construction of different epimeric intermediates from common starting materials. We anticipated that it would be possible to hydrolyzed the enol ether moiety of compound B in a distereodivergent matter, thus achieving the C2-C3 cis- or trans-configuration. From compound B our first C-C bond disconnection leads back to the N-acyliminium ion C. Based on our previous developments in stereoselective N-acyliminium ion cyclizations we proposed that the annulation could be controlled to give either the α- or β-epimer in a second diasterodivergent reaction.[26,27b] Further disconnections lead back to the α,β-unsaturated aldehyde 1 and β-ketoamide 2. We reasoned that optical activity could be introduced in the first step through an enantioselective organocatalytic conjugate addition (Scheme 1).[28] The catalytic asymmetric conjugate addition of amidomalonates to α,β-unsaturated aldehydes has been previously studied by Rios et al.[29] and our group.[27] However, this reaction is limited to cinnamic aldehyde derivatives and attempts to use alkyl-substituted α,β-unsaturated aldehydes resulted in decomposition of the aldehyde. This drastically limits the potential use of this reaction in quinolizidine natural product synthesis. We reasoned that the reluctance of amidomalonates to undergo conjugate addition to alkyl-substituted α,β-unsaturated aldehydes was mainly due to the poorer stability of alkyl-substituted α,β-unsaturated aldehydes compared to cinnamic aldehydes and the low nucleophilicity of the amidomalonate. In order to circumvent

this we attempted to use the more nucleophilic β-ketoamide in the conjugate addition.

OH

NAr

O*

N

Ar

O

*

HN

Ar

O

*

H

N

OHO

Ar

HN

OHO

Ar

H

HN OAr

O

+

OH

O

O

HN OAr

O

*

Diastereo-divergentannulation

Enantioselectiveconjugate addition

Diastereo-divergenthydrolysis

of enolether

trans-α-A cis-β-A

C

α-B β-B

1

2

N

OHO

Ar

HN

OHO

Ar

H

HHHH HH HH2 3 2 3 2 3 2 3

cis-α-A trans-β-A

Scheme 1. Stereodivergent retrosynthetic analysis of quinolizidine alkaloids.

One-Pot Stereoselective Construction of the Quinolizidine Carbon Skeleton: Our retrosynthetic analysis leads back to the α,β-unsaturated aldehyde 1 that was easily assessable through the cross-metathesis of acroleine and 3-butenol using only 0.7 mol% Grubbs 2:nd generation catalyst in almost quantitative yield. The β-ketoamides 2a-c were accessed through the condensation of t-butyl acetoacetate with the corresponding 2-arylethanamine (Scheme 2).

HOO Grubbs 2nd

DCM, refluxHO

O

(>99 %)1

NH

OO

H2Nt-BuO

O O ArArDioxane

90 °C2a Ar = 3-Indolyl (49 %)2b Ar = 3,4-dimethoxyphenyl (71 %)2c Ar = 2-thiophenyl (62 %)

Scheme 2. Starting material synthesis.

Gratifyingly, we found that β-ketoamides 2a-c smoothly reacted with the α,β-unsaturated aldehyde 1 in the presence of catalyst 3, giving a white precipitate that indicated that the conjugate addition had gone to completion. An analytical sample of the formed precipitate was analyzed by 1H-NMR, establishing it as a diastereomeric mixture of lactols 5a-c (Scheme 3). The crude reaction mixture containing the lactol 5a-c was quenched by addition of TFA to give a 1:1 mixture of the two ring junction isomers α-7a-c and β-7a-c that could be isolated in good yields and high enantioselectivity in a two-step one-pot process (Scheme 3 and

4

Table 1).[30] The mechanism for this reaction is proposed to proceeds through iminium ion activation and conjugate addition to give 4. The sterically shielding groups on the catalyst will shield the Re-face of the intermediate iminium ion, favoring nucleophilic attack of the β-ketoamides from the Si-face, generating the C1-stereocenter with the desired absolute configuration.[31] Spontaneous cyclization gives the intermediate lactol 5 (Scheme 3). Addition of TFA to lactol 5 triggers an acid catalyzed cascade reaction consisting of: lactol ring opening, enol ether formation, hemiaminal formation and acid catalyzed elimination of water to give N-acyliminium ion 6. Subsequent N-acyliminium ion cyclization gives a mixture of α-7a-c and β-7a-c.[32]

N

O

H

Oα-7a-c / β-7a-c99-92 % ee

O

HNO

ONH OTMS

PhPh

Ar

HO

1 2

(R)-3

Ar

N

Ar

O

OO

O

HN

ArO

H

H

H

O

HN

O

HO

H

NOTMS

PhPh

HO

Bottom face shielding

O

O

HN

ArOH

H

O TFA

5a-c4a-c 6a-c

Ar

1)

2) TFA

Scheme 3. Proposed mechanism for the one-pot quinolizidine synthesis.

The ring junction stereocenter is formed through the N-acyliminium ion cyclization: reactions that are known to be under kinetic control.[33] Through examination of the expected transition states in the N-acyliminium ion cyclization, we reasoned that the kinetically favored ring junction configuration should be formed through Si-face addition leading to formation of the β-epimer (Figure 4). Confident that the diastereoselectivity in this step could be controlled to favor selective formation of the α- or the β-ring junction epimer through kinetic or thermodynamic control, we set out to find a series of acid conditions for the one-pot cascade.

NO

H

kinetic

(Si-face addition)

thermodynamic

(Re-face addition)α-epimer

β-epimer

O

H

H

H

NO O

H

H

H

H

N

H

N

HH

H

OO

OO

Figure 4: Proposed transition states in the formation of thermodynamic and kinetic favored ring junction epimers in the N-acyliminium ion cyclization.

This turned out to be a considerably challenging task and no real trends could be observed, with most acids giving a close to 1:1 diastereomeric ratio.[34] After extensive screening we found a series of conditions that allowed for a diastereomeric switch (Table 1). Thus, quenching the reaction of β-ketoamide 2a with acetyl chloride

resulted in formation of a precipitate that was found to be the thermodynamically favored indolo[2,3-a]quinolizidine α-7a as the only observable isomer (Table 1, entry2). Interestingly, when using benzoyl chloride we observed a switch in diastereoselectivity and the kinetically favored product β-7a was obtained as the major isomer in 82:18 diastereoselectivity (Table 1, entry 3).

Table 1: Enantio and diastereoselective One-Pot formation of both ring junction epimers of the indolo[2,3-a], benzo[a] and thieno[3,2-a]quinolizidine skeleton. [a]

NO

H

NO

H

β-7a-c

O

O

α-7a-c

O

HNO

O NH OTMS

PhPh1)

2) Acid

Ar

HO

1 2

Kinetic

conditions

Thermodynamic

conditions(R)-3

Ar

Ar

H

HOne-Pot

Entry Ar Product Acid D.r.

[T/K][b]

e.e.

[%][c]

Yield

[%][d]

1

NH

TFA 50:50 92 80

2 α-7a AcCl >95:5 92 (99) [f]

85

3 β-7a BzCl[e] 18:82 92 (95) [f]

70

4 MeOOMe

α-7b Et3O.BF4 70:30 92 73

5 β-7b SnCl4 22:78 92 76

6

S α-7c Et3O.BF4 67:33 95 94

7 β-7c BzCl 33:67 94 78

[a] A solution of aldehyde 1 (1.2 equiv), amide 2 (1 equiv) and catalyst 3 (20 mol%) in

DCM (1 M) was stirred at room temperature. After full conversion of 2, the given acid

was added to the reaction mixture. [b] Determined by 1H NMR spectroscopy on the

crude reaction mixture. [c] Determined by chiral HPLC on the major diastereoisomer.

[d] Isolated combined yields of both epimers. [e] Benzoyl chloride was added at -78 °C

and stirred for 4 h before slowly allowed to reach room temperature O.N. [f] A solution

of aldehyde 1 (1.2 equiv), amide 2a (1 equiv) and catalyst 3 (20 mol%) in DCM (1 M) was stirred at -20 °C for 72 h.

It is also worth noting that the kinetically favored β-indolo[2,3-a]quinolizidine β-7a could be epimerized to the thermodynamically favored α-7a-epimer by treatment with refluxing TFA giving a ratio of 85:15 in favor of the α-epimer (Scheme 4). When subjecting the pure thermodynamically favored α-7a-epimer to refluxing TFA, the same thermodynamic equilibrium was reached. Since a higher preference for the α-7a-epimer was obtained using acetyl chloride then under thermodynamic equilibrium conditions (c.f. Table 1, entry 2 and Scheme 4), it appears as the acetyl chloride promoted N-acyliminium ion cyclization is not under thermodynamic control, leading us to believe that the high selectivity observed is due to the precipitation of the thermodynamically favored α-7a-epimer during the reaction. Unfortunately, the optimized acid conditions for the indole-compound could not be directly applied for selective ring junction formation of the benzo[a]- or the thieno[3,2-

5

a]quinolizidines 7b-c and a new acid screening was conducted. As for the initial screening of the indole-compound, the one-pot cascade using the phenyl- and thiophenyl-ketoamides 2b-c gave poor selectivity in the formation of the ring junction stereocenter using a variety of different acid conditions. Eventually we found that triethyloxonium tetrafluoroborate promoted formation of the thermodynamically favored ring junction stereocenter α-7b-c with moderate selectivity (Table 1, entries 4-6). One-pot conditions favoring the kinetic epimers benzo[a]- and thieno[3,2-a]quinolizidines β-7b-c with moderate selectivity was identified to be tin(IV)chloride and benzoyl chloride, respectively (Table 1, entries 5-7). The exact role of the acid with respect to selectivity in the formation of the ring junction stereocenter is not clear and we have not been able to detect any obvious trends between different acids during screening.[34]

N

O

HN

O

H

β-7aOO

α-7a

HH

HN HN

N

O

HN

O

H

β-7aOO

α-7a

HH

HN HNTFA

reflux

TFA

reflux

single isomer single isomer85:15 Scheme 4. Acid catalyzed epimerization of α- and β-indolo[2,3-a]quinolizidine 7a.

Preparation of functionalized quinolizidine intermediates: After establishing an efficient and stereoselective method for preparation of alkaloid carbon skeletons 7a-c, we started to investigate how these intermediates could be applied in total synthesis. In order to obtain the desired natural products, we needed to reduce both the amide carbonyl and the masked carbonyl group in the dihydropyran moiety. Our main focus from this point on was to develop an efficient methodology using as few reaction steps as possible, and to limit the number of isolations and purifications of reaction intermediates. We also needed to consider separation of the non-desired ring junction diastereoisomers as early as possible in the reaction sequence. It appeared that the α- and β-epimers of amides 7a-c could not be easily separated on flash column; however, reduction of the crude reaction mixture from the one-pot-cascade was accomplished by initial alkylation with triethyloxonium tetrafluoroborate, followed by NaBH4 reduction to give the corresponding amines 8a-c in high to moderate overall yields from their corresponding β-ketoamide 2 (Scheme 5). At this stage the α- and β-epimers of amines 8a-b could be easily separated by flash column.

1) Et3O.BF4, 2,6-di-tBu-pyridine DCM. r.t., 20h.

2) NaBH4, MeOH, 0 oC, 2h.

N

O

H

H

O

Ar

Crude reactionmixture

NH

H

O

Ar

FC separation ofα- and β-epimers

O

HNO

OAr

HO

1 2

Reactionconditions

in Table 1.

over all yield of pure isomer

81 %, 12b-α-8a Ar = indolo[2,3-a]54 %, 12b-β-8a Ar = indolo[2,3-a]63 %, 11b-α-8b Ar = benzo[a]66 %, 11b-β-8b Ar = benzo[a]65 %, 10b-α-8c Ar = thieno[3,2-a]57 %, 10b-β-8c Ar = thieno[3,2-a]

7a-c 8a-c

Scheme 5. Enantio- and diastereoselective synthesis of the quinolizidine skeleton.

Next we needed to open the dihydropyran moiety, bearing in mind selective formation of the final stereocenter. Treatment of the α-epimers of amines α-8a-c with HCl in water/THF at room temperature, exclusively gave the trans ring junction of the lactol α-trans-9a-c (Table 2, entries 1, 4 and 7. For nomenclature see Figure 3).

Table 2: Diastereodivergent lactol formation.[a]

NH

HN

H

O

H

O OH

H

Ar Ar

2M HClaq / THF NH

O

H

OH

Ar

H

α-trans-9a-cβ-trans-9a-c β-cis-9a-c

α-8a-cβ-8a-c

Entry Ar S.M. Temp.

[°C]

ratio: [b]

trans/cis

Product

1

NH

α-8a r.t. >95:5 α-trans-9a

2 β-8a 65 83:17 β-trans-9a

3 β-8a 0 20:80 β-cis-9a

4 MeO OMe

α-8b r.t. >95:5 α-trans-9b

5 β-8b 65 71:29 β-trans-9b

6 β-8b 0 5:95< β-cis-9b

7

S

α-8c rt >95:5 α-trans-9c

8 β-8c 65 72:28 β-trans-9c

9 β-8c 0 5:95< β-cis-9c

[a] Compound 6 was dissolved in 2 M HCl(aq.)/THF (1:3 c = 0.1 M) at the given

temperature. [b] Determined by 1H NMR spectroscopy on the crude reaction mixture.

The selective formation of this stereocenter is due to the thermodynamic stability of the all-equatorial quinolizidine structure and attempts to access the α-cis-configuration have failed (Scheme 6). However, hydration of the dihydropyran in the kinetic β-epimer series turned out to be under kinetic and thermodynamic control and treatment of benzo[a]quinolizidine and thieno[3,2-a]quinolizidine β-9b-c with HCl in water / THF at room temperature favored the cis-configuration between C2-C3 and gave a 2:1 mixture of β-cis-9b-c and β-trans-9b-c. Further optimization of the hydration revealed that treatment of β-8b-c with HCl in water / THF at 0 °C exclusively gave the C2-C3 cis-configuration and β-cis-9b-c were obtained as the only observed isomers (Table 2, entries 6 and 9). The indolo[2,3-a]quinolizidine β-8a reacted with lower selectivity in this reaction and gave a 4:1 mixture of β-cis-9a and β-trans-9a (Table 2, entry 3). Interestingly, lactol formation at elevated temperatures (HCl in water / THF at 65 °C) reversed the selectivity and favored formation of benzo[a]quinolizidine and thieno[3,2-a]quinolizidine β-trans-9b-c, in a 5:2 ratio (Table 2, entries 5 and 8). The indolo[2,3-a]quinolizidine β-8a showed higher selectivity under these reaction conditions and β-trans-9a was favored with a corresponding 5:1 dr (Table 2, entry 2). Furthermore, we found that the pure β-cis-9a-c

6

epimers could be smoothly epimerized in HClaq / THF at 65 °C to give β-trans-9a-c in the same diastereomeric ratio as was observed for the acid catalyzed hydration of β-9a-c, indicating that β-trans-9a-c is the thermodynamically favored isomer. Our assumption is that the epimerization is driven through the open keto-form to the more favored cyclohexane trans-configuration followed by re-lactonization (Scheme 6).

OH

H

OH

N

H

HH

NH

OH

H

NH

H

OHO

NH

HH

ON

HH

O

NH O

H

NH

H

H

O

OH

O

OHN

H

HH

OH

O

HCl

THF/H2O

HCl

THF/H2O

HCl THF/H2OEpimerization/Ring flip

Ringflip

α-8a-c α-trans−9a-c

β-8a-c β-trans−9a-c

β-cis−9a-cKinetic product

Thermodynamic product

Scheme 6. Stereoselective hydration of enol ether.

The β-cis-9a-c and the β-trans-9a-c epimers were easily separated by flash column and the β-cis-9a-c could again be epimerized to a 2:1 mixture of β-trans-9a-c and β-cis-9a-c through treatment with HCl in water/THF at 65 °C. The lactols were isolated by extraction with DCM. The DCM solution was partially concentrated and the resulting solution was treated with acetic anhydride to promote ring opening of the lactol to give the ketones 10a-c. The excess acetic anhydride was quenched by addition of methanol before the reaction mixture was treated with tosyl

hydrazide in AcOH / MeOH (1:3) to give the corresponding hydrazones (Scheme 7). Any undesired epimer from the previous hydration of enol ether 8 was separated by flash column and the hydrazones 11a-c were isolated as a single isomer in good to excellent overall yields from amine 8a-c without purification of synthetic intermediates.

All reactions from β-ketoamide 2 to the hydrazone intermediate 11 are remarkably clean and in most cases no by-products could be observed in the crude reaction mixtures by 1H-NMR. Although, it should also be pointed out that the β-trans-quinolizidine series was more difficult to handle compared to the α-trans- and β-cis-quinolizidine derivatives, in particular during purification by flash column, which is also reflected in the lower isolated yields of these compounds. The entire reaction sequence starting from β-ketoamide 2a-b and α,β-unsaturated aldehyde 1 was also preformed without any purification of synthetic intermediates on a multi-gram scale to give 12b-α-trans-11a as a single isomer in 63 % overall yield and 11b-α-trans-11a-b and 11b-β-cis-11a-b as a 1:1 mixture in 62 % combined overall yield (Scheme 8).

O

HO

11.20 g

12 mmol

2a-b10 mmol

Ar

HNO

ON

NNHTs

H

HNH

AcO

H

N

AcO

H

NNHTs

N

AcO

H

NNHTs

MeOOMe

MeOOMe

HH H H

See supportininformation

11b-α-trans-11b(1.69 g)

11b-β-cis-11b(1.69 g)

-one flash column-62 % combined overall yield-d.r. 1:1

See supportinginformation

-one flash column-63 % overall yield-single observable isomer

12b-α-trans-11a(2.61 g)

Scheme 8. Multi-gram syntheses of hydrazone intermediates 11a-b.

over all yield of pure isomer

77 %, 12b-α-trans-11a Ar = indolo[2,3-a]65 %, 12b-β-trans-11a Ar = indolo[2,3-a]73 %, 12b-β-cis-11a Ar = indolo[2,3-a]84 %, 11b-α-trans-11b Ar = benzo[a52 %, 11b-β-trans-11b Ar = benzo[a]79 %, 11b-β-cis-11b Ar = benzo[a]71 %, 10b-α-trans-11c Ar = thieno[3,2-a]57 %, 10b-β-trans-11c Ar = thieno[3,2-a]81 %, 10b-β-cis-11c Ar = thieno[3,2-a]

NH

H NH

O

H

OOH

HAc2O, DMAP

Pyr DCM

H2NNHTs / HCl

MeOH / AcOHN

AcO

H

NNHTs

Ar Ar Ar

N

AcO

H

O

Ar

Reactionconditions

in Table 2

Crude reactionmixture

Crude reactionmixture

9a-c 10a-c8a-c

HH H H

11a-c

Scheme 7. Stereodivergent syntheses of hydrazone intermediates 11a-c.

7

N

HO

H

H H

HN

N

HO

H

H H

MeOOMe

N

HO

H

H H

MeOOMe

N

HO

H

H H

MeOOMe

N

HO

H

H H

S

N

HO

H

H H

S

N

HO

H

H H

HN

N

HO

H

H H

MeOOMe

N

HO

H

H H

MeOOMe

N

HO

H

H H

S

NH

HNH

HO

H

(-)-Dihydrocorynantheol12b-α-trans-13

(74 % (47 % overallfrom 2a))

(+)-Hirsutinol12b-β-trans-13

(75 % (26 % overallfrom 2a))

(-)-Protoemetinol11b-α-trans-12

(92 % (49 % overallfrom 2b))

(+)-11b-epi-Protoemetinol11b-β-trans-12

(78 % (27 % overallfrom 2b))

(+)-3-epi-11b-epi-Protoemetinol11b-β-cis-12

(91 % (47 % overallfrom 2b))

10b-α-trans-14(82 % (38 % overall

from 2c))

10b-β-trans-14(68 % (31 % overall

from 2c))

(-)-Corynantheol12b-α-trans-16

(67 % (42 % overallfrom 2a))

Dehydroprotoemetinol11b-α-trans-17

(62 % (33 % overallfrom 2b)

11b-epi-Dehydroprotoemetinol

11b-β-trans-17(65 % (22 % overall

from 2b)

10b-α-trans-18(48 % (22 % overall

from 2c))

N

AcO

H

NNHTs

Ar

N

HO

H

Ar

N

HO

H

Ar

H H HH H HN

AcO

H

NHNHTs

Ar

H H

H15 11

N

HO

H

H H

HN

(+)-3-epi-Hirsutinol12b-β-cis-13

(97 % (38 % overallfrom 2a))

1) DIBAL-H, DCM, -78 °C.2) KOHaq

or1) NaBH3CN, HCl, DMF, 2) D,3) NaOHaq/MeOH/DCM.

n-BuLi

THF

Scheme 9. Preparation of a series of natural products, their analogs and epimers through full and partial hydrazone reduction.

Applications in Total Synthesis: We decided to proceed through the hydrazone intermediate because from here we have a choice between of full reduction to the saturated C3 alkyl chain or partial reduction under Shapiro conditions to give the C3 vinyl-group. The full reduction of benzo[a]-quinolizidine-hydrazones α-trans-11b and β-cis-11b to the ethyl group and the simultaneous reductive cleavage of the acetate moiety was accomplished using DIBAL-H. Full consumption of starting material was observed after 10 min at -78 °C in a clean and high yielding reaction giving the natural product (-)-Protoemetinol (11b-α-trans-12) in 92 % yield from 11b-α-trans-11b and 49 % overall yield from β-ketoamide 2b. In the same manner, the analogs 3-epi-11b-epi-Protoemetinol (11b-β-cis-12), 3-epi-Hirsutinol (12b-β-cis-13) and thieno[3,2-a]quinolizidine (10b-α-trans-14) were prepared in high yields (Scheme 9). On the other hand, DIBAL-H reduction of benzo[a]- and thieno[3,2-a]quinolizidine-hydrazones α-trans-11b-c was sluggish and after 10 min reaction time only the intermediate hydrazine 15 could be isolated, along with several unidentified byproducts. Prolonged reaction time at elevated temperature (DIBAL-H, 3 h, r.t.) slowly decomposed the hydrazine intermediate to the product in low yields. The hydrazine intermediate 15 was remarkably stable and could be isolated before it was thermally decomposed at 70 °C to the desired product in low yields. The α-trans- and β-trans-indolo[2,3-a]quinolizidine-hydrazones 11a also reacted with poor selectivity with DIBAL-H and gave low yields and mixtures of product and byproducts. After screening of different reducing agents we found that NaBH3CN in the presence of 3 equivalents of HCl cleanly reduced indolo[2,3-a]quinolizidine-hydrazones 12b-α-trans-11a and 12b-β-trans-11a, benzo[a]- and thieno[3,2-a]quinolizidine-hydrazones β-trans-11b-c to the corresponding hydrazines 15. The

intermediate hydrazines 15 were isolated by extraction and heated in DMF (100 °C) to decompose the hydrazine intermediate, followed by addition of KOHaq/ methanol / DCM to hydrolyze the acetate group, giving the natural product (-)-Dihydrocorynantheol (12b-α-trans-13) and (+)-Hirsutinol (12b-β-trans-13) as well as the analogs (+)-11b-epi-Protoemetinol (11b-β-trans-12) and thieno[3,2-a]quinolizidine 10b-β-trans-14 in good overall yields (Scheme 9). As previously mentioned, the hydrazone moiety also provides access to a vinyl-group at the C3 position through partial reduction under Shapiro conditions. Thus, treatment of hydrazones α-trans-11 and β-trans-11 with n-BuLi resulted in elimination of the hydrazone and deacetylation providing access to the natural product (-)-Corynantheol (12b-α-trans-16) and the analogs Dehydroprotoemetinol (11b-α-trans-17), 11b-epi-Dehydroprotoemetinol (11b-β-trans-17) and thieno[3,2-a]quinolizidine 10b-α-trans-18 in moderate to good yields (Scheme 9).

The hydroxy-quinolizidines were smoothly oxidized using Dess-Martin periodinane to give the naturally occurring alkaloids (-)-Dihydrocorynantheal (12b-α-trans-19), (-)-Corynantheal (12b-α-trans-20) and (-)-Protoemetine (11b-α-trans-21) and the analogs (+)-11b-epi-Dehydroprotoemetine (11b-β-trans-22) and thieno[3,2-a]quinolizidine 10b-α-trans-23 in overall high yields (Scheme 10).

8

N

HO

N

O

Dess Martinperiodinane

DCM, r.t.

Ar Ar

H

H H

H

H H

NH

HNH

O

HN

H

HNH

O

H

NH

H

MeOOMe

O

HN

H

H

MeOOMe

O

H N

O

H

H H

S

10b-α-trans-23(78 %)

11b-epi-Dehydroprotoemetine

11b-β-trans-22(90 %)

(-)-Protoemetine11b-α-trans-21

(92 %)

(-)-Corynantheal12b-α-trans-20

(82 %)

(-)-Dihydrocorynantheal12b-α-trans-19

(78 %)

Scheme 10. Natural product synthesis.

(-)-Protoemetine occupies a key position among the ipec alkaloids since it is considered to be an intermediate in the biogenesis of emetine and several related alkaloids.[35] Thus, the quinolizidine aldehydes 19-23 are useful synthetic precursors for further transformation into a broad variety of quinolizidine natural products of higher structural complexity. For example, the methodology described here represents an efficient formal synthesis of (–)-Emetine,[36] (-)-Cephaeline,[36,37] (–)-Tubulosine[38] and (–)-deoxy-tubulosine[39] through the Pictet-Spengler annulation of (-)-Protoemetine 21 with 3,4-dimethoxyphenylethylamine, O-methyldopamine, serotonin and tryptamine, respectively (Scheme 11). Furthermore, Jones oxidation of Dihydrocorynantheal 19 in methanol gives the corresponding methyl ester;[40] subsequent formylation and methylation provides an efficient formal synthesis of (+)-Dihydrocorynantheine (Scheme 12).[41] The same approach should also provide access to Hirsutine and Corynantheine from Hirsutinol and Corynantheal.

N

O

H

H H

MeOOMe

N

R

H

H H

MeOOMe

R =

HNOMe

OR'

H

HNH H

N

ref. 36-39(-)-Emetine (R'= Me)(-)-Cephaeline (R'= H)

(-)-Tubulosine (R'= OH)(-)-Deoxytubulosine (R'= H)

(-)-Protoemetine11b-α-trans-21 R'

Scheme 11. The formal synthesis of (–)-Emetine, Cephaeline, (–)-Tubulosine and (–)-Deoxytubulosine from (-)-Protoemetine 11b-α-trans-21.

N

O

H

H H

HN

N

MeO

H

H H

HN

O

MeO

(+)-Dihydrocorynantheine

ref 40

N

MeO

H

H H

HN

O

ref 41

(-)-Dihydrocorynantheal12b-α-trans-20

Scheme 12. The formal synthesis of (+)-Dihydrocorynantheine from (-)-Dihydrocorynantheal 12b-α-trans-19.

This methodology was also applied in the protecting group free total synthesis of (-)-(15S)-Hydroxydihydrocorynantheol 12b-α-trans-24, an alkaloid isolated in 1999 from an endemic tree of Puerto Rico, Antirhea Portoricensis (Rubiaceae).[42] Lactol 12b-α-trans-9a was prepared without purifications of intermediates and the crude compound was dissolved in methanol/DCM and directly reduced with NaBH4 to give an 81:19 mixture of diols in high yields (Scheme 13). By comparing the 1H-NMR data of the major isomer with literature data we were able to conclude that this was the non-natural epimer (15R)-Hydroxydihydrocorynantheol 12b-α-trans-24. However, opening of the lactol 12b-α-trans-9 to the ketone 12b-α-trans-10 and subsequent reduction using L-Selectride gave the natural product (-)-(15S)-Hydroxydihydrocorynantheol 12b-α-trans-24 with 77:23 diastereoselectivity and 50 % combined overall yield from β-ketoamide 2a.[43]

NH

O

H

OH

H

HN

NH

HO

H

HO

H

HN

NaBH4MeOH(88 %)

O

HNO

O

HO

1 2

NH

57 % overall yielddr. 81:19

NH

HO

H

HO

H

HN

50 % overall yielddr. 77:23

N

AcO

H

O

H H

HN

L-SelectrideTHF

(89%)

(-)-(15S)-Hydroxy-dihydrocorynantheol

12b-α-trans-24

1515

(-)-(15R)-Hydroxy-dihydrocorynantheol

12b-α-trans-24

12b-α-trans-9a 12b-α-trans-10a

Scheme 13. Purification and protecting group free total synthesis of natural product (-)-(15S)-Hydroxydihydrocorynantheol 12b-α-trans-24 and its epimer (15R)-Hydroxydihydrocorynantheol.

Conclusion

Here is described the development of a highly efficient and enantioselective synthetic strategy that allows for access to a broad number of optically active quinolizidine alkaloids of the Coryananthein and Ipec family on a multigram scale. The optical activity is introduced by asymmetric catalysis starting from easy

9

available non-chiral starting materials and the following two stereocenters are introduced through diastereodivergent reactions. By employing diastereodivergent steps, selective access to 3 out of 4 possible optically active diastereomers can be realized from common starting materials using the same synthetic strategy. The focus during the development of this strategy has been on efficiency and major attention has been invested in excluding protection groups and finding reaction conditions compatible with a limited number of isolation and purification steps. Most of the reaction steps are extremely high yielding and the potential of this methodology in natural product synthesis is demonstrated by the total synthesis of (-)-Dihydrocorynantheol in 47 % overall yield, (-)-Protoemetinol in 49 % overall yield and (-)-Corynantheol in 42 % overall yield from easy accessible α,β-unsaturated aldehyde 1 and β-ketoamide 2. Furthermore, this methodology also provides easy access to an array of epimers and analogs not accessible through synthetic elaboration of naturally occurring alkaloids, which is exemplified by the synthesis of the thieno[3,2-a]quinolizidine natural product analogs as well as the synthesis of the β-cis-quinolizidine series. This synthetic strategy also provides easy access to the natural products (-)-Dihydrocorynantheal, (-)-Corynantheal, (-)-Protoemetine and different analogs thereof in high overall yields. We also describe the total synthesis of (-)-(15S)-Hydroxydihydrocorynantheol and the formal synthesis of (–)-Emetine, (-)-Cephaeline, (–)-Tubulosine, (–)-deoxy-tubulosine and (+)-Dihydrocorynantheine. The major benefits of this strategy are the easy available starting materials, common synthetic strategy, stereodivergent reaction steps, omission of protection groups and limited isolations and purifications of reaction intermediates. Due to efficiency, product diversity and operational simplicity, this protocol has the potential to find important use in natural product synthesis, biochemistry and pharmaceutical science.

Experimental Section

Purification free multi-gram preparation of hydrazone 12b-α-trans-11a.β-Ketoamide 2a (2.44 g, 10 mmol) and (R)-catalyst 3 (650 mg, 2 mmol) was dissolved in DCM (10 mL). To this solution was added 5-hydroxyl-pentaldehyde 1 (1.20 g, 1.2 mmol) and the resulting reaction mixture was stirred until a white or white/brown precipitate was formed that indicates full conversion. Acetyl chloride (100 mmol, 7.10 ml) was added and the mixture was stirred O.N. at room temperature. The reaction was quenched by addition of saturated NaHCO3 (aq.) and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) followed by addition of di-tert-butylpyridine (5.70 g, 35 mmol) and Et3O.BF4 (3.80 g, 25 mmol). After 4 h was DCM removed under vacuum and the residue re-dissolved in methanol (150 mL) and cold to 0 oC. NaBH4 (2.30 g, 60 mmol) was added in small portions and the resulting mixture was stirred for 1 hour at room temperature. Methanol was removed under vacuum and the residue was dissolved in THF (100 ml) and 2 M HCl (aq.) (100 mL). The mixture was stirred O.N. before being quenched with sat. NaHCO3 and NaOH (10 mL, 5 % aqueous solution). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4). DCM was removed under vacuum until approx. 100 mL remained. Pyridine (8.0 g, 100 mmol), DMAP (30 mg, 0.2 mmol) and acetic anhydride (10 g, 100 mmol) were added to this solution in turn. The reaction was left for 4 h at room temperature before sat. NaHCO3 was added. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4). The solvent was removed and the residue was dissolved in methanol (120 mL) and acetic acid (40 mL) followed by addition of tosylhydrazide (3.72 g, 20 mmol). The reaction was stirred overnight at room temperature before being quenched with sat. NaHCO3. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified with column chromatography to give 12b-α-trans-11a as a yellow solid. (2.77 g, overall yield: 53 %).

(-)-Dihydrocorynantheol 12b-α-trans-15: To a solution of the hydrazone 12b-α-trans-11a and NaBH3CN (2.2 equiv) in DMF (c = 0.1 M) was added HCl (3 equiv., 1M in Et2O) dropwise at 0 °C. The resulting mixture was stirred at room temperature O.N. and quenched with Na2CO3(aq.) (2 M). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give a solution of the crude tosyl-hydrazine in DMF. The DMF solution was

heated at 100 °C for 45 min. before being cooled down to room temperature. DCM (10 ml/mmol), MeOH (10 ml/mmol) and KOHaq (1M, 10 ml/mmol) were added and the resulting mixture was stirred vigorously for 2h before being dispersed between DCM and water. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH) to give the title compound in 74 % overall yield. [α]20

D = -13.5 (CDCl3, c = 0.004) (Lit: [α]20D = -20.4 (CDCl3, c = 0.25)). All

characterization data was in accordance with those previously reported.[44,45]

(-)-Corynantheol 12b-α-trans-16: The hydrazone compound 12b-α-trans-11a was dissolved in anhydrous THF (c = 0.1 M) under nitrogen atmosphere and cooled down to -78 °C. n-BuLi (5 equiv. 2.3 M in hexane) was added dropwise to this solution. During the addition the reaction mixture turned from yellow to brown and resulting solution was allowed to slowly reach room temperature and stirred overnight. Brine (5 mL) was added to quench the reaction and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH) to give the title compound in 67 % yield according to the general procedure described above. [α]20

D = -65.0° (CDCl3, c = 0.05) (Lit: [α]20

D = -61°). All characterization data was in accordance with those previously reported.[46]

Acknowledgements

This work was made possible by a grant from The Swedish Research Council (VR) and The Royal Swedish Academy of Sciences (KVA). W.Z. thanks The Carl Trygger Foundation for Scientific Research for a grant.

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[18] For selected examples of non-asymmetric cascade/one-pot reaction to quinolizidine derivatives see; a) H. Fang, X. Wu, L. Nie, X. Dai, J. Chen, W. Cao, G. Zhao, Org. Lett. 2010, 12, 5366. b) Y. Li, T. Kobayashi, S. Katsumura, Tetrahedron Lett. 2009, 50, 4482. c) L. F. Tietze, N. Tölle, C. N. Pilling, Synlett, 2008, 525. d) A. W. Pilling, J. Boehmer, D. J. Dixon, Angew. Chem. Int. Ed. 2007, 46, 5428. e) M. Y. Chang, Y.-C. Chen, W.-S. Chung, M.-R. Tasib, N.-C. Chang, Tetrahedron Lett. 2005, 61, 585. f) M. M. Abelman, J. K. Curtis, D. R. James, Tetrahedron Lett. 2003 44, 6527. g) P. Jakubec, M. Helliwell, D. J. Dixon, Org. Lett. 2008, 10, 4267.

[19] a) B. J. English, R. M. Williams, J. Org. Chem. 2010, 75, 7869. b) L. F. Tietze, N. Rackelmann, G. Sekar, Angew. Chem. Int. Ed. 2003, 42, 4254.

[20] For recent general reviews see: a) L.-F. Tietze, G. Brasche, K. M. Gericke, Domino reactions in organic synthesis; Wiley-VCH, Weinheim, 2006. b) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993. c) C. J. Chapman, C. G Frost, Synthesis 2007, 1, 1. For recent reviews on organocatalytic domino reactions, see: d) I. Andrea-Nekane, C. Xavier, V. Monica, R. Ramon, Current Organic Chemistry 2009, 13, 1432. e) X. Yu, W. Wang, Org. Biomol. Chem. 2008, 6, 2037. f) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. Int. Ed. 2008, 47, 6138. g) D. Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. Int. Ed. 2007, 46, 1570.

[21] (a) H. Ishikawa, M. Honma, Y. Hayashi, Angew. Chem. Int. Ed. 2011, 50, 2824. (b) H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. Int. Ed. 2009, 48, 1304. (c) S. Zhu, S. Yu, Y. Wang, D. Ma, Angew. Chem. Int. Ed. 2010, 49, 4656. d) A. Michrowska, B. List, Nature Chemistry 2009, 1, 225.

[22] D. W. C. MacMillan, A. M. Walji, Synlett 2007, 1477.

[23] D. Stærk, P.-O. Norrby, J. W. Jaroszewski, J. Org. Chem. 2001, 66, 2217.

[24] H. Masumiya, T. Saitoh, Y. Tanaka, S. Horie, N. Aimi, H. Takayama, H. Tanaka, K. Shigenobu, Life Sciences 1999, 65, 2333.

[25] G. Stork, P. C. Tang, M. Casey, B. Goodman, M. Toyota, J. Am. Chem. Soc. 2005, 127, 16255.

[26] For reviews see: a) B. E. Maryanoff, H. Zhang, J. H. Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104, 1431. b) J. Royer, M. Bonin, L. Micouin, Chem. Rev. 2004, 104, 2311.

[27] (a) J. Franzén, A. Fisher, Angew. Chem. Int. Ed. 2009, 48, 787. (b) W. Zhang, J. Franzén, Adv. Synth. Catal. 2010, 352, 499.

[28] For recent reviews on organocatalytic conjugate addition, see for example: a) A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107, 5416. b) J. L. Vicario, D. Badía, L. Carillo, Synthesis 2007, 2065. c) D. Almasi, D. A. Alonso, C. Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299. d) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701.

[29] G. Valero, J. Schimer, I. Cisarova, J. Vesely, A. Moyano, R. Rios, Tetrahedron Lett. 2009, 50, 1943.

[30] The conjugate addition of 1 to 2a-c have been optimized with respect to catalysts solvents and reaction temperature and in all cases lower yields and enantioselectivity was observed.

[31] The absolute configuration was established by comparing optical rotation of the synthesized natural products with literature values.

[32] The exact order in which enol ether formation and N-acyliminium ion cyclization occurs has not been established.

[33] a) B. E. Maryanoff, D. F. McComsey, B. A. Duhl-Emswiler, J. Org. Chem. 1983, 48, 5062. b) M. Node, H. Nagasawa, K. Fuji, J. Am. Chem. Soc. 1987, 109, 7901. c) M. Lounasmaa, M. Berner, A. Tolvanen, Heterocycles 1998, 48, 1275.

[34] For a complete acid screening see supporting information.

[35] F. Weygand, G. Eberhard, Angew. Chem. 1952, 64, 458.

[36] C. Szántay, L. Take, P. Kolonits, J. Org. Chem. 1966, 31, 1447.

[37] A. R. Battersby, B. J. T. Harper, J. Chem. Soc. 1959, 1748.

[38] C. Szántay, G. Kalaus, Chem. Ber. 1969, 102, 2270.

[39] K. N. Rao, R. K. Bhattacharya, S. R. Venkatachalam, Anti-Cancer Drugs 1998, 9, 727.

[40] E. Seguin, M. Koch, Helvetica Chim. Act. 1980, 63, 1335.

[41] (a) R. L. Beard, A. I. Meyers, J. Org. Chem. 1991, 56, 2091. (b) S. Yu, O. M. Berner, J. M. Cook, J. Am. Chem. Soc. 2000, 122, 7827.

[42] B. Weiniger, R. Anton, J. Nat. Prod. 1994, 57, 287.

[43] Reduction of ketone 12b-α-trans-10 with NaBH4 (MeOH, 0°C) and DIBAL-H (DCM, -78 °C) gave (15S)-Hydroxydihydrocorynantheol (15S)-12b-α-trans-24 / (15R)-Hydroxydihydrocorynantheol (15R)-12b-α-trans-24 in a 32:68 and 42:58 diastereomeric ration, respectively.

[44] L. Richard, A, Beard, I. Meyers, J. Org. Chem. 1991, 56, 2091.

[45] M. Ihara, K. Yasui, N. Taniguchi, K. Fukumoto, J. Chem. Soc., Perkin Trans 1, 1990, 1469.

[46] G. Massiot, P. Thepenier, M. J. Jacquier, L. Le Men-Olivier, R. Verpoorte, C. Delaude, Phytochemistry 1987, 26, 2839.

11

Entry for the Table of Contents Natural Product Synthesis

N

NH

OH

H HN

MeO

MeOOH

H HH H

HN

O

Ar

O

+

OH

O

AsymmetricCatalysis

Cascade /One-pot

Diastereo-divergent

NoProtecting

Groups

N

OH

HH

HS

+ Synthesis

of Epimers

& Analogs

Thieno-analog(-)-Protoemetinol (-)-Dihydrocorynantheol

N

NH

O

H HH

N

MeO

MeOO

H HH

(-)-Protoemetin

(-)-Corynantheal

29 %(overall)49 %

(overall) 47 %(overall)

35 %(overall)

45 %(overall)

N

MeO

MeOOH

H HH

(+)-11b-epi-Protoemetinol

49 %(overall)

(+)-3-epi-11b-epi-Protoemetinol

N

MeO

MeOOH

H HH

49 %(overall)

N

NH

OH

H HH

(+)-Hirsutinol

26 %(overall)

N

NH

OH

H HH

(+)-3-epi-Hirsutinol

38 %(overall)

N

NH

OH

H HH

(-)-Corynantheol

42 %(overall)

Wei Zhang, Juho Bah, Andreas Wohlfarth, Johan Franzén* ………..… Page – Page

A Stereodivergent Strategy for the Preparation of Corynantheine and Ipecac Alkaloids, there Epimers and Analogs: Efficient Total Synthesis of (-)-Dihydrocorynantheol, (-)-Corynantheol, (-)-Protoemetinol, (-)-Corynantheal, (-)-Protoemetine and Related Natural and Non-Natural alkaloids.

Total synthesis: It’s easy! Efficiency: one-pot/cascade reactions, asymmetric catalysis, no protecting groups and limited isolation and purification of synthetic intermediates. Diversity: implementation of two diastereodivergent reaction-steps.

Together: a general and common synthetic strategy for the preparation of the title alkaloids and related natural products, their epimers and several non-natural analogs in excellent overall yields on multi-gram scale.

S1

A Stereodivergent Strategy for the Preparation of Corynantheine and Ipecac Alkaloids, there Epimers and Analogs: Efficient Total

Synthesis of (-)-Dihydrocorynantheol, (-)-Corynantheol, (-)-Protoemetinol, (-)-Corynantheal, (-)-Protoemetine and Related Natural

and Non-Natural Compounds.

Wei Zhang, Juho Bah, Andreas Wohlfarth and Johan Franzén*.

Department of Chemistry, Organic Chemistry,Royal Institute of Technology (KTH), Teknikringen 30, SE-100 44 Stockholm, Sweden

jfranze@kth.se

Supporting Information Table of Contents Experimental Section: S2 Optimization of Acid conditions for the N-Acyliminium ion Cyclization: S21 NMR-Spectra : S24

S2

Experimental Section General. The 1H NMR and 13C NMR spectra were recorded at 500 or 400 MHz and 125 or 100 MHz, respectively. The chemical shifts are reported in ppm relative to CHCl3 (δ = 7.26) for 1H NMR and relative to the central CDCl3 resonance (δ = 77.0) for 13C NMR. Flash chromatography (FC) and column chromatography were carried out using Merck silica gel 60 (230-400 mesh). Materials. All the catalysts and chemicals are commercially available and used as received unless otherwise noticed. All solvents were of p.a. quality and used without further purification unless otherwise noticed. All reactions are preformed without pre-dried solvents in open vessels unless otherwise noticed. (E)-5-hydroxypent-2-enal 1:

OH + O 1 mol% Grubbs' 2nd Gen.CH2Cl2, rt HO O

A solution of freshly distilled acrolein (22.2 ml, 332 mmol), 3-buten-1-ol (7.16 ml, 83.2 mmol), and Grubbs catalyst 2nd generation (550 mg, 0.65 mmol, 0.78 mol%) was stirred in dry DCM (30 mL) at r. t. for 24 h (monitored by 1H NMR). The dark-brown mixture was directly submitted to column chromatography (SiO2, Et2O 100 %) to achieve the product as a yellow liquid (7.3 g, quantitative yield, caution volatile). 1H NMR (500 MHz, CDCl3): ™ 9.53 (d, J = 8.0 Hz, 1H), 6.90 (dt, J = 15.5 Hz, 7.0 Hz, 1H), 6.20 (ddt, J = 15.5 Hz, 7.5 Hz, 1.5 Hz, 1H), 3.85 (dd, J = 6.5, 6.5 Hz, 2H), 2.61 (tdd, J = 6.5 Hz, 6.0 Hz, 1.5 Hz, 2H), 1.65 (br s, 1H). General procedure for the preparation of β-ketoamides 2: Ar NH2 +

O

O

OAr

HN

O Odioxane.

90 oC To a pre-heated solution of tert-butyl acetoacetate (600mg, 0.6 mmol) in dioxane (10 mL) at 90 oC was added a solution of the corresponding amine (0.2 mmol) in dioxane (10 mL) dropwise over 30 min. The reaction was stirred at 90 oC until all amine was consumed (approximately 0.5 h, monitored by TLC). Dioxane and excess tert-butyl acetoacetate were removed under vacuum. The residue was directly submitted to column chromatography (SiO2, EtOAc 100 %) to give the pale yellow solid. The solid was washed repeatedly with diethyl ether and filtered to remove the trace impurity to give the pure product as a white or pale yellow solid. (Precaution: The purity of the amides is crucial for the next reaction step. Without repeated wash of the solid product with diethyl ether we suspect that the amides still contains minor amounts of undetectable impurities (>1 %) that drastically disturbs the conjugate addition. Every new batch of amide should be tested in a small-scale reaction (0.1 mmol) before scaling up).

HN

O OHN N-(2-(1H-indol-3-yl)ethyl)-3-oxobutanamide 2a: The title compound was prepared from tryptamine and tert-butyl acetoacetate in 49 % yield according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 8.14 (br s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 (t, d = 7.5 Hz,

S3

1H), 7.13 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 6.91 (br s, 1H), 3.62 (q, J = 6.5 Hz, 2H), 3.34 (s, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.22 (s, 3H). 13C NMR (100 MHz, CDCl3): ™ 204.6, 165.4, 136.4, 127.3, 122.2, 122.1, 119.5, 118.7, 112.9, 111.3, 49.8, 39.8, 31.0, 25.2.

HN

O O

MeO

MeO N-(3,4-dimethoxyphenethyl)-3-oxobutanamide 2b: The title compound was prepared from 2-(3,4-dimethoxyphenyl)ethylamine and tert-butyl acetoacetate in 71 % yield according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 6.94 (br s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.51 (q, J = 6.5 Hz, 2H), 3.38 (s, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3): ™ 204.6, 165.4, 149.0, 147.7, 131.3, 120.7, 112.0, 111.4, 55.9, 55.8, 49.7, 40.9, 35.2, 31.1.

HN

O OS N-(2-(thiophen-2-yl)ethyl)- 3-oxobutanamide 2c: The title compound was prepared from 2-thiopheneethylamine and tert-butyl acetoacetate in 62 % yield according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 7.17 (dd, J = 1.0 Hz, 5.0 Hz, 1H), 7.05 (br s, 1H), 6.95 (dd, J = 3.5 Hz, 5.0 Hz, 1H), 6.85 (dd, J = 0.5 Hz, 3.5 Hz, 1H), 3.55 (q, J = 6.0 Hz, 2H), 3.40 (s, 2H), 3.05 (t, J = 6.0 Hz, 2H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3): ™ 203.9, 165.0, 140.5, 126.5, 124.8, 123.4, 49.1, 40.4, 30.4, 29.2. General procedure for the enantioselective One-pot preparation of the quinolizidine skeleton:

Ar

NHO

O

+

OH

O

1) 20 mol% cat*, DCM, rt.2) Acid: Kinetic conditions

1) 20 mol% cat*, DCM, rt.2) Acid: Thermodynamic conditions

N

O

O

H

H

N

O

O

H

H NH

PhPh

OTMScat*

Ar

Ar

N

O

H

H

R1) 2.5 equiv. Et3O.BF4, 3.5 equiv. DTBP DCM, rt.

N

2) 6 equiv. NaBH4, MeOH, 0 oC

2,6-di-tert-butylpyridineDTBP

N

O

H

H

R1) 2.5 equiv. Et3O.BF4, 3.5 equiv. DTBP DCM, rt.

2) 6 equiv. NaBH4, MeOH, 0 oC

To a solution of the corresponding β-ketoamide 2 (1 equiv) and catalyst 3 (20 mol%) in dichloromethane (c = 1 M) was added (E)-5-hydroxypent-2-enal 1 (1.2 equiv.). The mixture was left at room temperature until the β-ketoamide was completely consumed and a white precipitate was formed (approximately 20 min. to 1 h). To this reaction mixture was added the indicated acid at room temperature for the given time as specified for each compound. Aqueous sat. NaHCO3 was added to quench the reaction and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product that was directly used in the next step without further purification. The diastereomeric ratio was determined by 1H NMR on the crude product. Analytical samples of pure products were obtained by FC or preparative HPLC. To a solution of the corresponding crude amide in DCM (c = 0.1 M) was added di-tert-butylpyridine (3 equiv.) and triethyloxonium tetrafluroborate (2 equiv.) in turn. The reaction was stirred at room temperature until all starting material was consumed (monitored by 1H NMR, approximately 4-6 h). DCM was removed by evaporation

S4

under vacuum. The residue was dissolved in methanol (c = 0.2 M) and cooled to 0 °C and to this solution was carefully added NaBH4 (6 equiv.) in several portions. The reaction was stirred for one additional hour at 0 °C and then quenched with carefully addition of brine. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The bridgehead diastereoisomers were separated by FC (EtOAc/MeOH).

N

O

O

H

H

HN

Compound 12b-α-7a (thermodynamic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2a using acetyl chloride (10 equiv. over night) a single observable diastereomer 12b-α-7a (thermodynamic) in 85 % yield and 92 % ee according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 7.75 (br s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (td, J = 8.0 Hz, 1.0 Hz, 1H), 7.12 (td, J = 8.0 Hz, 1.0 Hz, 1H), 5.24-5.17 (m, 1H), 4.83 (dm, J = 11.5 Hz, 1H), 4.24 (ddd, J = 10.5 Hz, 3.5 Hz, 2.5 Hz, 1H), 3.93 (tm, J = 11.5 Hz, 1.5 Hz, 1H), 2.86 (m, 2H), 2.79-2.73 (m, 1H), 2.73-2.67 (m, 1H), 2.52 (ddd, J = 12.5 Hz, 4.5 Hz, 3.0 Hz, 1H), 2.32 (d, J = 1.5 Hz, 3H), 2.05 (dm, J = 13.0 Hz, 1H), 1.64-1.56 (m, 1H), 1.55 (dt, J =12.5 Hz, 12.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 164.9, 162.3, 136.2, 133.6, 127.0, 122.1, 119.9, 118.5, 110.8, 110.0, 103.7, 65.5, 53.5, 40.2, 35.5, 29.8, 29.1, 21.3, 20.5. The enantiomers were separated by HPLC on Chiralcel OJ-RH column (150x4.6 mm) with H2O / acetonitrile as the eluent (70:30 to 20:80 (60 min. gradient), flow rate: 0.25 mL/min): Rt (min): 47.4 (major); 57.5 (minor).

N

O

O

H

H

HN

Compound 12b-β-7a (kinetic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2a using benzoyl chloride (1.2 equiv. -78 °C for 3h then slowly to room temperature O.N.) in 70 % total yield of 12b-β75a and 12b-α-7a, dr. 82:18 and 92 % ee according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 7.97 (br s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.17 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7. 11 (td, J = 7.5 Hz, 1.0 Hz, 1H), 5.09 (dm, J = 12.5 Hz, 1H), 4.93 (br m, 1H), 4.13 (ddd, J = 11.0 Hz, 4.0 Hz, 3.0 Hz, 1H), 3.74 (tm, J = 11.5 Hz, 1H), 3.02 (tdd, J = 12.0 Hz, 4.5 Hz, 2.5 Hz), 2.94 (td, J = 12.5 Hz, 3.0 Hz, 1H), 2.67 (dm, J = 14.0 Hz, 1H), 2.42-2.34 (m, 2H), 2.25 (d, J = 1.5 Hz, 3H), 2.00-1.90 (m, 2H), 1.64-1.56 (m, 1H). 13C NMR (125 MHz, CDCl3): ™ 166.4, 161.7, 135.8, 133.4, 127.6, 122.1, 119.9, 118.4, 111.6, 111.0, 104.7, 65.3, 53.4, 43.0, 32.9, 29.3, 27.5, 21.0, 20.0. The enantiomers were separated by HPLC on Chiralcel OJ-RH column (150x4.6 mm) with H2O / acetonitrile as the eluent (70:30 to 20:80 (60 min. gradient), flow rate: 0.25 mL/min): Rt (min): 41.8 (major); 57.5 (minor).

S5

N

O

O

OO

H

H

Compound 11b-α-7b (thermodynamic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2b using Et3O-BF4 (2.0 equiv. over night) in 73 % total yield of 11b-α-7b (thermodynamic) and 11b-β-7b (kinetic), dr. 70:30 and 92% ee according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 6.66 (s, 1H), 6.62 (s, 1H), 4.92 (ddd, J = 12.5 Hz, 4.5 Hz, 2.5 Hz, 1H), 4.67 (dd, J = 12.0 Hz, 4.5 Hz, 1H), 4.24 (ddd, J = 10.5 Hz, 3.5 Hz, 2.5 Hz, 1H), 3.96-3.91 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.95-2.88 (m, 1H), 2.81 (td, J = 12.0 Hz, 3.0 Hz, 1H), 2.70-2.65 (m, 1H), 2.64 (dt, J = 16.0 Hz, 3.0 Hz, 1H), 2.60 (ddd, J = 12.5 Hz, 4.0 Hz, 3.5 Hz, 1H), 2.32 (d, J = 1.0 Hz, 3H), 2.04 (dm, J = 11.5 Hz, 1H), 1.60 (tm, J = 13.0 Hz, 1H), 1.41 (dt, J = 12.0 Hz, 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 164.9, 161.7, 129.5, 127.7, 111.6, 108.1, 103.8, 65.6, 56.1, 56.0, 55.9, 39.9, 37.4, 30.0, 29.2, 28.7, 20.2. MS (APCI): m/z (%): 330.1 (100) [M+H]+. The enantiomers were separated by HPLC on Chiralcel OJ-RH column (150x4.6 mm) with H2O / acetonitrile as the eluent (70:30 to 20:80 (90 min. gradient), flow rate: 0.25 mL/min): Rt (min): 37.8 (minor); 40.8 (major).

N

O

O

OO

H

H

Compound 11b-β-7b (kinetic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2b using SnCl4 (1.0 M in CH2Cl2, 5.0 equiv. over night) in 76 % total yield of 11b-β-7b (kinetic) and 11b-α-7b (thermodynamic), dr. 78:22 and 92 % ee according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 6.66 (s, 1H), 6.63 (s, 1H), 4.84 (ddd, J = 12.5 Hz, 5.5 Hz, 1.5 Hz, 1H), 4.64 (t, J = 4.5 Hz, 1H), 4.18 (dtd, J = 11.0 Hz, 3.0 Hz, 2.5 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.85-3.80 (m, 1H), 3.08-3.01 (m, 1H), 2.89 (dt, J = 7.5 Hz, 4.0 Hz, 1H), 2.61 (dm, J = 16.0 Hz, 1H), 2.45 (td, J = 13.0 Hz, 4.0 Hz, 1H), 2.42-2.36 (m, 1H), 2.24 (d, J = 1.5 Hz, 3H), 1.94-1.86 (m, 2H). 13C NMR (125 MHz, CDCl3): ™ 166.4, 160.7, 148.0, 147.5, 129.1, 128.9, 112.2, 107.6, 104.9, 65.6, 56.3, 55.9, 55.1, 41.9, 34.3, 29.3, 28.4, 27.2, 19.7. MS (APCI): m/z (%): 330.1 (100) [M+H]+. The enantiomers were separated by HPLC on Chiralcel OD-RH column (150x4.6 mm) with H2O / acetonitrile as the eluent (70:30 to 20:80 (60 min. gradient), flow rate: 0.25 mL/min): Rt (min): 34.4 (minor); 39.9 (major).

N

O

O

H

H

S

Compound 10b-α-7c (thermodynamic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2c using Et3O-BF4 (2.0 equiv. over night) in 94 % total yield of 10b-α-7c (thermodynamic) and 10b-β-7c (kinetic), dr. 67:33 and 95% ee according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 7.11 (d, J = 5.5 Hz, 1H), 6.80 (d, J = 5.0 Hz, 1H), 5.17-5.13 (m, 1H), 4.62 (dm, J = 11.5 Hz, 1H), 4.22 (ddd, J = 10.5 Hz, 3.5 Hz, 2.0 Hz, 1H),

S6

3.91 (tm, J = 11.5 Hz, 1H), 2.97-2.89 (m, 1H), 2.80 (t, J = 13.5 Hz, 2H), 2.64 (tm, J = 12.5 Hz, 1H), 2.54 (ddd, J = 13.0 Hz, 5.0 Hz, 3.5 Hz, 1H), 2.30 (d, J = 1.5 Hz, 3H), 2.02 (ddt, J = 13.5 Hz, 6.0 Hz, 2.0 Hz, 1H), 1.60-1.51 (m, 1H) 1.39 (dt, J = 12.0 Hz, 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 165.3, 162.3, 136.8, 135.1, 124.0, 123.8, 104.2, 65.9, 56.0, 40.3, 37.0, 30.0, 29.4, 25.5, 20.6. The enantiomers were separated by HPLC on Chiralcel OJ-RH column (150x4.6 mm) with H2O / acetonitrile as the eluent (70:30 to 20:80 (60 min. gradient); 20:80 (isocratic 15 min); flow rate: 0.25 mL/min): Rt (min): 33.7 (major); 38.9 (minor).

N

O

O

H

H

S

Compound 10b-β-7c (kinetic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2c using benzoyl chloride (2.0 equiv. over night) in 78 % total yield of 11b-β-7c (kinetic) and 10b-α-7c (thermodynamic), dr. 67:33 and 94 % ee according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 7.11 (d, J = 5.0 Hz, 1H), 6.80 (d, J = 5.5 Hz, 1H), 5.02 (ddd, J = 13.0 Hz, 6.0 Hz, 1.0 Hz, 1H), 4.67 (br m, 1H), 4.16 (ddd, J = 10.5 Hz, 3.5 Hz, 2.5 Hz, 1H), 3.78 (dm, J = 12.0 Hz, 1H), 3.08 (tm, J = 14.0 Hz, 1H), 2.90 (td, J = 12.5 Hz, 4.0 Hz, 1H), 2.72 (dd, J = 16.0 Hz, 4.0 Hz, 1H), 2.44 (ddd, J = 13.0 Hz, 3.0 Hz, 2.0 Hz, 1H), 2.32 (tm, J = 12.5 Hz, 1H), 2.24 (d, J = 1.5 Hz, 3H), 1.94-1.85 (m, 2H), 1.62-1.54 (m, 1H). 13C NMR (125 MHz, CDCl3): ™ 166.0, 161.4, 136.8, 136.7, 123.0, 122.9, 104.9, 65.5, 55.2, 42.4, 33.9, 29.3, 27.3, 24.7, 20.0. The enantiomers were separated by HPLC on Chiralcel OJ-RH column (150x4.6 mm) with H2O / acetonitrile as the eluent (70:30 to 20:80 (60 min. gradient); 20:80 (isocratic 15 min); flow rate: 0.25 mL/min): Rt (min): 32.6 (major); 37.8 (minor).

N

O

H

HNH

Compound 12b-α-8a (thermodynamic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2a using acetyl chloride (10 equiv. over night) according to the general procedure described above. 12b-α-8a (thermodynamic) was isolated as a single isomer in 81 % overall yield after FC. 1H NMR (500 MHz, CDCl3): ™ 7.94 (br s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.0 Hz, 1H), 7.08 (t, J = 7.0 Hz, 1H), 3.02 (dt, J = 10.5, 4.0 Hz, 1H), 3.83 (td, J = 10.5, 2.5 Hz, 1H), 3.69 (d, J = 12.5 Hz, 1H), 3.44 (d, J = 11.5 Hz, 1H), 3.19 (ddd, J = 11.0, 5.5, 1.3 Hz, 1H), 3.07-3.00 (m, 1H), 2.95 (d, J = 12.5 Hz, 1H), 2.78 (d, J = 15.5 Hz, 1H), 2.69 (td, J = 11.0, 4.5 Hz, 1H), 2.31 (br m, 1H), 2.19 (ddd, J = 12.5, 4.5, 3.0 Hz, 1H), 2.04-1.98 (m, 1H), 1.83 (s, 3H), 1.65-1.58 (m, 1H), 1.39 (dt, J = 12.0, 12.0 Hz, 1H).13C NMR (125 MHz, CDCl3): ™ 145.9, 136.2, 134.7, 127.6, 121.7, 119.6, 118.4, 110.9, 108.5, 106.0, 64.7, 59.7, 56.7, 37.6, 32.3, 30.8, 21.8, 16.4. MS (APCI): m/z (%): 295.1 (100) [M+H]+.

S7

N

O

H

HNH

Compound 12b-β-8a (kinetic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2a using benzoyl chloride (1.2 equiv. -78 °C for 3h then slowly to room temperature O.N.) according to the general procedure described above. 12b-β-8a (kinetic) was isolated in 54 % overall yield as a single isomer after FC. 1H NMR (500 MHz, CDCl3): ™ 7.87 (br s, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 4.44 (br s, 1H), 3.97 (m, 1H), 3.74 (tdd, J = 10.5 Hz, 2.5 Hz, 1.5 Hz, 1H), 3.36 (dt, J = 13.5 Hz, 4.0 Hz, 1H), 3.29 (d, J = 13.5 Hz, 12.0 Hz, 2H), 3.24 (dt, J = 15.0 Hz, 5.5 Hz, 1H), 3.08 (m, 1H), 2.62 (ddd, J = 16.0 Hz, 5.0 Hz, 1.0 Hz, 1H), 2.22 (ddd, J = 13.5 Hz, 3.5 Hz, 3.0 Hz, 1H), 2.07-1.96 (m, 2H), 1.85 (td, J = 13.0 Hz, 5.5 Hz, 1H), 1.80 (s, 3H), 1.60 (m, 1H). 13C NMR (MHz, CDCl3): ™ 145.8, 135.9, 133.0, 128.0, 121.8, 119.8, 118.3, 111.0, 108.5, 106.5, 64.1, 54.1, 51.4, 47.2, 35.7, 30.7, 27.2, 17.4, 16.3. MS (APCI): m/z (%): 295.1 (100) [M+H]+.

N

O

H

H

MeOOMe

Compound 11b-α-8b (thermodynamic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2b using Et3O-BF4 (2.0 equiv. over night) according to the general procedure described above. 11b-α-8b (thermodynamic) was isolated in 63 % yield as a single isomer after FC. 1H NMR (500 MHz, CDCl3): ™ 6.65 (s, 1H), 6.56 (s, 1H), 4.03 (dt, J = 11.0 Hz, 4.0 Hz, 1H), 3.87-3.82 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.61 (d, J = 13.0 Hz, 1H), 3.31 (d, J = 11.0 Hz, 1H), 3.10-3.01 (m, 2H), 2.92 (d, J = 12.5 Hz, 1H), 2.71-2.67 (m, 1H), 2.59-2.53 (m, 1H), 2.34-2.27 (m, 1H), 2.04-2.00 (m, 1H), 1.81 (s, 3H), 1.67-1.59 (m, 1H), 1.26 (dt, J= 12.0 Hz, 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 147.4, 147.1, 145.2, 129.9, 126.7, 111.4, 108.3, 105.9, 64.7, 62.3, 57.3, 56.0, 55.8, 51.5, 39.1, 32.6, 30.8, 29.1, 16.2. MS (APCI): m/z (%): 316.1 (100) [M+H]+.

N

O

H

H

MeOOMe

Compound 11b-β-8b (kinetic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2b using SnCl4 (1.0 M in CH2Cl2, 5.0 equiv. over night) according to the general procedure described above. 11b-β-8b (kinetic was isolated in 66 % yield as a single isomer after FC. 1H NMR (500 MHz, CDCl3): ™ 6.68 (s, 1H), 6.58 (s, 1H), 3.99-3.93 (m, 2H), 3.85 (s, 3H), 3.85 (s, 3H), 3.79 (td, J = 10.0 Hz, 2.0 Hz, 1H), 3.33 (d, J = 12.5 Hz, 1H), 3.18 (dd, J = 12.0 Hz, 5.5 Hz, 1H), 3.12 (d, J = 12.5 Hz, 1H), 3.08 (dd, J = 17.0 Hz, 5.5 Hz, 1H), 2.99 (td, J = 12.0 Hz, 4.5 Hz, 1H), 2.50 (dd, J = 16.0 Hz, 4.0 Hz, 1H), 2.32-2.23 (m, 2H), 1.99-1.94 (m, 1H), 1.76 (dt, J = 12.0 Hz, 6.0 Hz, 1H), 1.75 (s, 3H), 1.61-1.54 (m, 1H). 13C NMR (125 MHz, CDCl3): ™ 147.6, 147.5, 144.6, 129.1, 126.8, 111.8, 109.0,

S8

106.5, 64.2, 57.0, 56.2, 55.9, 51.2, 49.8, 37.0, 30.6, 26.3, 24.8, 16.0. MS (APCI): m/z (%): 316.1 (100) [M+H]+.

N

O

H

S

H

Compound 10b-α-8c (thermodynamic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2c using Et3O-BF4 (2.0 equiv. over night) according to the general procedure described above. 10b-α-8c (thermodynamic) was isolated as a single isomer in 65 % yield as a single isomer after FC. 1H NMR (500 MHz, CDCl3): ™ 7.06 (d, J = 5.0 Hz, 1H), 6.79 (d, J = 5.0 Hz, 1H), 4.02 (ddd, J = 10.5 Hz, 4.5 Hz, 3.5 Hz, 1H), 3.83 (td, J = 10.5 Hz, 2.5 Hz, 1H), 3.60 (d, J = 12.5 Hz, 1H), 3.19-3.07 (m, 3H), 2.85 (d, J = 12.5 Hz, 1H), 2.80 (dd, J = 15.0 Hz, 1H), 2.62 (td, J= 10.5 Hz, 3.5 Hz, 1H), 2.32-2.24 (m, 2H), 2.04-1.98 (m, 1H), 1.81 (s, 3H), 1.66-1.59 (m, 1H), 1.23 (dt, J = 12.0 Hz, 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 145.6, 137.2, 133.7, 123.9, 122.7, 105.9, 64.6, 61.6, 56.4, 52.4, 38.8, 32.2, 30.6, 25.5, 16.2. MS (APCI): m/z (%): 262.2 [M+H]+.

N

O

H

S

H

Compound 10b-β-8c (kinetic conditions): The title compound was prepared from (E)-5-hydroxypent-2-enal 1 and amide 2c using benzoyl chloride (2.0 equiv. over night) according to the general procedure described above. 10b-β-8c (kinetic) was isolated in 57 % yield as a single isomer after FC. 1H NMR (500 MHz, CDCl3): ™ 7.12 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 4.13 (br m, 1H), 3.96 (ddd, J = 11.0 Hz, 5.5 Hz, 3.0 Hz, 1H), 3.76 (td, J = 10.0 Hz, 2.5 Hz, 1H), 3.32-3.28 (m, 1H), 3.22-3.08 (m, 4H), 2.65 (dm, J = 16.0 Hz, 1H), 2.27 (ddd, J = 13.0 Hz, 4.5 Hz, 4.0 Hz, 1H), 2.05 (broad, m, 1H), 1.99-1.93 (m, 1H), 1.78 (s, 3H), 1.74 (td, J = 12.5 Hz, 5.5 Hz, 1H), 1.59-1.53 (m, 1H). 13C NMR (125 MHz, CDCl3): ™ 146.0, 134.2, 133.3, 124.7, 122.8, 106.0, 64.2, 56.0, 50.7, 47.1, 36.5, 30.4, 26.3, 20.5, 16.1. MS (APCI): m/z (%): 262.3 (100) [M+H]+.

S9

General procedure for the preparation of quinolizidine hydrazones:

N

O OH

N

O

2N HCl (aq.)/THF (1:3)

65 oC

Ac2O,Pyridine,

DMAPDCM

N

AcO O

N

AcO NNHTs

TsNHNH2,

MeOH/AcOH (3:1)

H

H H H

N

O OH

Ac2O,Pyridine,

DMAPDCM

N

AcO O

N

AcO NNHTs

TsNHNH2,

MeOH/AcOH (3:1)

H H H

N

O OH

Ac2O,Pyridine,

DMAPDCM

N

AcO O

N

AcO NNHTs

TsNHNH2,

MeOH/AcOH (3:1)

H H H

H H

H H

H H

H

H H H

H H H

H H H

H H H

Ar Ar Ar

ArArAr

Ar Ar Ar

Ar

2N HCl (aq.)/THF (1:3)

0 oC

2N HCl (aq.)/THF (1:3)

0 oC

β-H

β-H

α-H

The corresponding quinolizidine substrate 8 was dissolved in 2 M HCl(aq.)/THF (1:1 c = 0.1 M) according to the conditions specified for each compound. The reaction mixture was quenched with Na2CO3(aq.) (2 M) and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was dissolved in DCM and cooled down to 0 oC. DMAP (10 mol%), pyridine (5 equiv.) and acetic anhydride (dropwise addition, 5 equiv.) were added in this order and the reaction was left at room temperature for 4h. MeOH (20 equiv.) was added to quench the reaction followed by addition of NaHCO3 (sat. aq.). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was dissolved in MeOH / AcOH (3:1, c = 0.2 M) and tosylhydrazide (2 equiv.) was added in one portion. The mixture was stirred at room temperature overnight. NaHCO3 (sat. aq.) was added and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC.

N

NNHTs

H

HNH

AcO

H

Compound 12b-α-trans-11a: The title compound was prepared by dissolving 12b-α-8a in 2 M HCl(aq.)/THF at room temperature and stirred for 2h. Continuing according to the general procedure gave 12b-α-trans-11a as a single observable isomer in 77 % overall yield. 1H NMR (500 MHz, CDCl3): ™ 7.84 (d, J = 8.1 Hz, 2H), 7.82 (br s, 1H), 7.46 (d, J = 7.9 Hz, 1H) 7.36 (br s, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.31 (d, J =8.1 Hz, 2H), 7.14 (t, J = 7.9 Hz, 1H), 7.08, (t, J = 7.9 Hz, 1 H) 3.99 (ddd, J = 8.5, 5.5, 2.0 Hz, 1H), 3.26 (d, J = 14.1 Hz, 2 H), 3.03 (m, 1H), 2.95 (dd, J = 11.5, 4.0 Hz) 2.71 (d, J = 14.6 Hz, 1H) 2.59 (td, J = 12.1, 5.4 Hz, 1H), 2.44 (td, J = 11.5, 4.0 Hz, 1H), 2.42 (s, 3H), 2.28 (t, J = 11.1, 2.2 Hz 1H) 2.24 (m, 1 H) 2.06 (s, 3H), 1.90 (m, 1H), 1.80 (s, 3H), 1.60 (m, 1H), 1.32 (td J = 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 171.3, 156.9, 144.2, 136.2, 135.6, 129.8, 129.6, 128.7,

S10

128.3, 121.7, 119.7, 118.3, 111.0, 108.4, 62.0, 59.4, 59.2, 52.9, 51.1, 34.9, 34.8, 32.3, 21.9, 21.7, 15,3. MS (APCI): m/z (%): 523.1 (100) [M+H]+.

N

NNHTs

H

HNH

AcO

H

Compound 12b-β-trans-11a: The title compound was prepared by dissolving 12b-β-8a in 2 M HCl(aq.)/THF and refluxed at 65 °C for 4h. Continuing according to the general procedure gave 12b-β-trans-11a and 12b-β-cis-11a in 65 % overall combined yield, dr. 83:17. 12b-β-trans-11a and 12b-β-cis-11a was separated by FC (EtOAc/MeOH). 1H NMR (500 MHz, CDCl3): ™ 8.58 (br s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 4.77 (dt, J = 11.3, 2.3 Hz, 1H), 4.38 (m, 1H), 3.40 (dt, J = 11.3, 4.3 Hz, 1H), 3.25-3.16 (overlapping peaks, 2H), 2.34 (m, 1H), 2.64-2.56 (overlapping peaks, 3H), 2.49 (t, J = 10.8 Hz, 1H), 2.31 (td, J = 10.3, 3.5 Hz, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 1.75 (dddd, J = 16.7, 11.2, 4.8, 2.9 Hz, 1H), 1.64 (s, 3H), 1.62 (ddd, J = 13.8, 11.7, 4.7 Hz, 1H), 1.48 (apparent q, J = 10.5 Hz, 1H), 1.17 (dt, J = 14.0, 10.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 172.8, 157.0, 143.9, 136.0, 135.2, 132.4, 129.2, 127.7, 127.5, 121.5, 119.4, 118.0, 111.1, 107.1, 60.8, 53.8, 51.2, 50.6, 49.5, 32.8, 31.2, 29.1, 21.5, 21.1, 17.3, 15.0. MS (APCI): m/z (%): 523.1 (100) [M+H]+.

N

NNHTs

H

HNH

AcO

H

Compound 12b-β-cis-11a: The title compound was prepared by dissolving 12b-β-8a in 2 M HCl(aq.)/THF at 0 °C and stirred for 4h. Continuing according to the general procedure gave 12b-β-cis-11a and 12b-β-trans-11a in 73 % overall combined yield, dr. 83:17. 12b-β-cis-11a and 12b-β-trans-11a was separated by FC (EtOAc/MeOH). 1H NMR (MHz, CDCl3): ™ 7.94 (br s, 1 H), 7.85 (d, J = 8.2 Hz, 2 H), 7.46 (d, J = 7.7 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.13 (t, J = 7.7 Hz, 1H) 7.07 (t, J = 7.7 Hz, 1H), 4.01 (m, 1 H), 3.94 (dt, J = 11.2, 5.8, 1H), 3.41 (br d, J = 11.4 Hz, 1H), 3.05 (m, 1H), 2.96 (m, 1 H), 2.87 (dd, J = 12.0, 2.9 Hz, 1H), 2.77-2.62 (overlapping peaks, 3H), 2.68 (q, J = 11.5 Hz, 1H), 2.45 (s, 3 H), 2.21 (m, 1H), 2.11 (td, J = 13.4, 2.7 Hz, 1H), 2.04 (s, 3 H), 1.80-1.72 (overlapping peaks including s at 1.70, 4H), 1.58 (ddt, J = 15.1, 10.8, 5.6 Hz, 1H), 1.19 (m, 1H). 13C NMR (125 MHz, CDCl3): ™ 171.2, 157.0, 144.1, 136.0, 135.3, 134.1, 129.4, 128.1, 127.3, 121.4, 119.4, 118.0, 110.8, 107.5, 62.5, 54.1, 53.2, 52.2, 47.7, 32.7, 29.8, 25.4, 21.6, 21.5, 21.0, 14.8. MS (APCI): m/z (%): 523.2 (100) [M+H]+.

N

NNHTs

H

H

MeOOMe

AcO

H

Compound 11b-α-trans-11b: The title compound was prepared by dissolving 11b-α-8b in 2 M HCl(aq.)/THF at room temperature and stirred for 2h.

S11

Continuing according to the general procedure gave 11b-α-trans-11b as a single observable isomer in 84 % overall yield. 1H NMR (500 MHz, CDCl3): ™ 7.84 (d, J = 8.5 Hz, 1H), 7.74 (br s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 3.94 (t, J = 7.0 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.11 (br d, J = 11.0 Hz, 1H), 3.06-2.99 (m, 1H), 2.88 (dd, J = 11.5 Hz, 4.0 Hz, 2H), 2.60 (br d, J = 16.0 Hz, 1H), 2.46 (td, J = 11.5 Hz, 4.0 Hz, 1H), 2.42 (s, 3H), 2.38 (td, J = 11.5 Hz, 4.0 Hz, 1H), 2.32 (ddd, J = 13.0 Hz, 3.0 Hz, 3.0 Hz, 1H), 2.23 (t, J = 11.0 Hz, 1H), 2.03 (s, 3H), 1.89-1.82 (m, 1H), 1.80 (s, 3H), 1.53-1.46 (m, 1H), 1.28-1.22 (m, 1H), 1.18 (dt, J = 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 171.0, 157.4, 147.6, 147.3, 144.0, 135.5, 129.5, 128.1, 126.6, 111.5, 108.2, 62.3, 62.1, 59.9, 56.1, 55.9, 51.8, 50.4, 36.5, 35.6, 32.4, 29.2, 21.6, 21.1, 15.1. MS (APCI): m/z (%): 544.2 (100) [M+H]+.

N

NNHTs

H

H

MeOOMe

AcO

H

Compound 11b-β-trans-11b: The title compound was prepared by dissolving 11b-β-8b in 2 M HCl(aq.)/THF and refluxed at 65 °C for 4h. Continuing according to the general procedure gave 11b-β-trans-11b and 11b-β-cis-11b in 65 % overall combined yield, dr. 71:29. 11b-β-trans-11b and 11b-β-cis-11b was separated by FC (EtOAc/MeOH). 1H NMR (500 MHz, CDCl3): ™ 7.65 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.62 (s, 1H), 6.59 (s, 1H), 4.13-4.04 (m, 2H), 3.87 (s, 6H), 3.81-3.73 (m, 1H), 3.04-2.97 (m, 2H), 2.89-2.83 (m, 1H), 2.75-2.63 (m, 2H), 2.52 (dm, J = 16.0 Hz, 1H), 2.36 (br m, 1H), 2.32 (s, 3H), 2.11-2.08 (br m, 1H), 2.04 (s, 3H), 1.95-1.90 (br m, 1H), 1.79 (s, 3H), 1.78-1.74 (m, 1H), 1.70-1.65 (m, 1H), 1.56 (br m, 1H). 13C NMR (125 MHz, CDCl3): ™ 171.0, 147.7, 147.6, 143.5, 129.3, 127.8, 115.0, 111.8, 108.4, 62.3, 56.7, 56.2, 55.9, 51.5, 50.8, 32.1, 31.6, 29.9, 21.5, 21.0, 15.3. MS (APCI): m/z (%): 544.1 (100) [M+H]+.

N

NNHTs

H

H

MeOOMe

AcO

H

Compound 11b-β-cis-11b: The title compound was prepared by dissolving 11b-β-8b in 2 M HCl(aq.)/THF at 0 °C and stirred for 4h. Continuing according to the general procedure gave 11b-β-cis-11b as a single observable isomer in 79 % overall yield. 1H NMR (MHz, CDCl3): ™ 7.8 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.61 (s, 1H), 6.59 (s, 1H), 4.02 (ddd, J = 11.5, 8.4, 5.6 Hz, 1H), 3.92 (dt, J = 11.5, 5.9 Hz, 1H), 3.85 (s, 1H), 3.24 (broad d, J = 11.3 Hz, 1H), 3.07 (ddd, J = 15.9, 11.4, 6.2 Hz, 1H), 2.96 (dd, J = 11.3, 5.7 Hz, 1H), 2.84 (dd, J = 12.3, 3.6 Hz, 1H), 2.73 (dt, J = 11.6, 3.7 Hz, 1H), 2.65 (dd, J = 16.1, 3.2 Hz, 1H), 2.59 (overlapping peaks, 2H), 2.45 (s, 3H), 2.25 (overlapping peaks, 2H), 2.05 (s, 3H), 1.78 (s, 3H), 1.61 (overlapping peaks, 2H), 1.20 (m, 1H). 13C NMR (MHz, CDCl3): ™ 171.0, 157.5, 147.6, 147.2, 144.1, 135.3, 129.5, 129.4, 128.2, 127.1, 111.6, 108.1, 62.9, 56.9, 56.1, 55.8, 53.1, 52.6, 47.5, 34.8, 31.6, 29.2, 25.3, 21.6, 21.0, 14.8. MS (APCI): m/z (%): 544.2 (100) [M+H]+.

S12

N

NNHTs

H

H

S

AcO

H

Compound 10b-α-trans-11c: The title compound was prepared by dissolving 10b-α-8c in 2 M HCl(aq.)/THF at room temperature and stirred for 2h. Continuing according to the general procedure gave 10b-α-trans-11c as a single observable isomer in 71 % overall yield. 1H NMR (500 MHz, CDCl3): ™ 7.83 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.23 (br s, 1H), 7.08 (d, J = 5.0 Hz, 1H), 6.78 (d, J = 5.0 Hz, 1H), 3.97-3.88 (m, 2H), 3.10-3.05 (m, 2H), 2.96 (dd, J = 11.5 Hz, 6.5 Hz, 1H), 2.90 (dd, J = 11.0 Hz, 3.5 Hz, 1H), 2.76 (dm, J = 14.0 Hz, 1H), 2.56 (td, J = 11.0 Hz, 4.0 Hz, 1H), 2.43 (s, 3H), 2.39 (td, J = 11.5 Hz, 3.5 Hz, 1H), 2.28 (ddd, J = 13.0 Hz, 3.0 Hz, 3.0 Hz, 1H), 2.25 (q, J = 11.0 Hz, 1H), 2.03 (s, 3H), 1.91-1.81 (m, 1H), 1.78 (s, 3H), 1.53-1.47 (m, 1H), 1.28-1.21 (m, 1H), 1.19 (td, J = 12.0 Hz, 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): ™ 171.0, 157.0, 144.1, 136.9, 135.4, 133.7, 129.5, 128.2, 123.8, 122.9, 62.2, 61.4, 58.9, 52.4, 50.9, 36.2, 35.1, 32.2, 25.6, 21.6, 21.0, 15.0. MS (APCI): m/z (%): 490.0 (100) [M+H]+.

N

NNHTs

H

H

S

AcO

H

Compound 10b-β-trans-11c: The title compound was prepared by dissolving 10b-β-8c in 2 M HCl(aq.)/THF and refluxed at 65 °C for 4h. Continuing according to the general procedure gave 10b-β-trans-11c and 10-β-cis-11c in 57 % overall combined yield, dr. 72:28. 10b-β-trans-11c and 10b-β-cis-11c was separated by FC (ETOAc/MeOH). 1H NMR (MHz, CDCl3): ™ 7.68 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 5.0 Hz, 1H), 7.09 (d, J = 7.5 Hz, 2H), 6.74 (d, J = 5.0 Hz, 1H), 4.11-3.98 (m, 2H), 3.77 (broad m, 1H), 3.07-2.84 (m, 2H), 2.87 (broad d, J = 11.0 Hz, 1H), 2.67-2.55 (m, 3H), 2.36 (s, 3H), 2.30 (dd, J = 6.0, 3.9 Hz, 1H), 2.09-1.98 (m, 1H), 2.04 (s, 3H), 1.84 (m, 1H), 1.76 (s, 3H), 1.70-1.59 (m, 2H), 1.49 (m, 1H) ppm. 13C-NMR: (125 MHz, CDCl3): ™ 171.1, 157.5, 143.6, 135.4, 133.7, 129.3, 127.8, 124.1, 122.4, 62.3, 56.0, 51.6, 50.3, 48.7, 32.7, 31.4, 29.8, 22.1, 21.6, 21.0, 15.2. MS (APCI): m/z (%): 490.0 (100) [M+H]+.

N

NNHTs

H

H

S

AcO

H

Compound 10b-β-cis-11c: The title compound was prepared by dissolving 10b-β-8c in 2 M HCl(aq.)/THF at 0 °C for 4h. Continuing according to the general procedure gave 10b-β-cis-11c as a single observable isomer in 81 % overall yield. 1H NMR (MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 5.2 Hz, 1H), 6.71 (d, J = 5.2 Hz, 1H), 3.98-3.83 (m, 2H), 3.16 (broad d, J = 11.3 Hz, 1H), 3.03-2.96 (m, 2H), 2.82 (dd, J = 11.9, 3.1 Hz, 1H), 2.76 (dd, J = 15.0, 3.6 Hz, 1H), 2.70 (ddd, J = 11.3, 3.6, 3.5 Hz, 1H), 2.69-2.60 (m, 1H), 2.56 (dd, J = 11.7, 11.6 Hz, 1H), 2.43 (s, 3H), 2.23-2.11 (m, 2H), 2.01 (s, 3H), 1.75 (s, 3H), 1.62 (ddd, J = 13.0, 12.0, 3.6 Hz, 1H), 1.52 (m, 1H), 1.13 (m, 1H). 13C-NMR: (125 MHz, CDCl3): δ 171.0, 157.7, 143.8, 136.7, 135.3, 133.8, 129.3, 128.0, 123.6, 122.7, 62.7, 56.0, 52.8, 52.1, 47.5, 34.1, 31.1, 25.3, 24.9, 21.5, 20.9, 14.9. MS (APCI): m/z (%):

S13

490.0 (100) [M+H]+. Full reduction of quinolizidine hydrazones. General procedure A:

N

AcO NNHTs

N

HO

1) 5 equiv.DIBAL-H, THF, 0 oC-rt.

2) KOHaq

Ar Ar

H

H H

H

H H

The hydrazone compound 11 was dissolved in anhydrous DCM (c = 0.1 M) under nitrogen atmosphere and cooled down to -78 °C. DIBAL-H (5 equiv. 1.0 M in DCM) was added dropwise and the resulting solution was stirred at -78 °C for 20 min. KOHaq (1 M, 30 equiv.) was added at -78 °C and the mixture was vigorously stirred for 2 h at room temperature (in order to dissociate the product from alumina). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH). General procedure B:

N

AcO NNHTs

N

HO

1) NaBH3CN, HCl, DMF2) Δ

3) NaOH/MeOH/DCM

Ar Ar

H

H H

H

H H

To a solution of the hydrazone 11 and NaBH3CN (2.2 equiv) in DMF (c = 0.1 M) was added HCl (3 equiv., 1M in Et2O) dropwise at 0 °C. The resulting mixture was stirred at room temperature O.N. and quenched with Na2CO3(aq.) (2 M). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give a solution of the crude tosyl-hydrazine in DMF. The DMF solution was heated at 100 °C for 45 min. before being cooled down to room temperature. DCM (10 ml/mmol), MeOH (10 ml/mmol) and KOHaq (1M, 10 ml/mmol) were added and the resulting mixture was stirred vigorously for 2h before being dispersed between DCM and water. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH).

N

HO

H

H H

HN

(-)-Dihydrocorynantheol 12b-α-trans-15: The title compound was prepared from 12b-α-trans-11a in 74 % yield according to the general procedure B described above. [α]20

D = -13.5 (CDCl3, c = 0.004) (Lit: [α]20D = -20.4 (CDCl3, c =

0.25)). All characterization data was in accordance with those previously reported.12

1 Richard, L.; Beard, A.; Meyers, I. J. Org. Chem. 1991, 56, 2091. 2 Ihara, M.; Yasui, K.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans 1, 1990, 1469.

S14

N

HO

H

H H

HN

(+)-Hirsutinol 12b-β-trans-15: The title compound was prepared from 12b-β-trans-11a in 73 % yield according to the general procedure A described above. 1H NMR (500 MHz, CDCl3): ™ 8.05 (br s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 4.01 (m, 1H), 3.77 (overlapping peaks, 2H), 3.64 (m, 1H), 3.15 (m, 1H), 3.02-2.94 (overlapping peaks, 2H), 2.71 (dd, J = 11.5, 3.2 Hz, 1H), 2.61 (br d, J = 11.5 Hz, 1H), 2.55 (dd, J = 11.5, 7.0 Hz, 1H), 2.17 (ddd, J = 13.7, 6.8, 4.2 Hz, 1H), 1.87 (ddd, J = 13.7, 7.4, 5.1 Hz, 1H), 1.76 (ddd, J = 13.4, 7.8, 4.2 Hz, 1H), 1.57-1.45 (overlapping peaks, 2H), 1.36 (m, 1H), 1.28 (m, 1H), 0.86 (t, J = 7.4 Hz, 1H). 13C-NMR: (125 MHz, CDCl3): δ 135.9, 133.9, 127.6, 121.3, 119.4, 118.0, 110.9, 107.9, 60.9, 54.5, 52.2, 52.0, 41.5, 35.2, 32.5, 31.7, 24.5, 19.0, 11.8. [α]20

D = 125 (Pyridine, c = 0.002) (Lit: [α]20D = 158

(Pyridine, c = 0.25)). All characterization data was in accordance with those previously reported.3

N

HO

H

H H

HN

(+)-3-epi-Hirsutinol 12b-β-cis-15: The title compound was prepared from 12b-β-cis-11a in 90 % yield according to the general procedure A described above. 1H NMR (500 MHz, CDCl3): ™ 7.79 (br s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 3.80 (overlapping peaks, 2H), 3.07 (m, 1H), 3.00 (m, 1H), 2.79 (dd, J = 11.4, 3.6 Hz, 1H), 2.70 (br d, J = 15.4 Hz, 1H), 2.64 (m, 1H), 2.29 (br t, J = 10.5 Hz, 1H), 2.14 (dt, J = 13.0, 2.7 Hz, 1H), 2.06 (m, 1H), 1.75-1.63 (overlapping peaks, 4H), 1.34-1.24 (overlapping peaks, 2H), 0.94 (t, J = 7.5 Hz, 3H). MS (APCI): m/z (%): 299.3 (100) [M+H]+. [α]20

D = 100 (CDCl3, c = 0.03).

N

HO

H

H

H

MeOOMe

(-)-Protoemetinol 11b-α-trans-12: The title compound was prepared from 11b-α-trans-11b in 92 % yield according to the general procedure A described above. [α]20

D = -46.6 (CDCl3, c = 0.006) (Lit: [α]16D = -54 (CHCl3, c = 0.18)). All

characterization data was in accordance with those previously reported.4

3 a) Lounasmaa, M.; Jokela, R.; Tirkkonen, B.; Miettinen, J.; Halonen, M. Heterocycles 1992, 34, 321.

b) Gomez-Pardo, D.; Desmaële, D.; d'Angelo, J. Tetrahedron Lett. 1992, 33, 6633. c) Kametani, T.; Kanaya, N.; Honda, T. Heterocycles 1981, 16, 1937. d) Sawa; M. Tetrahedron 1970, 26, 2931.

4 (a) Nuhant, P.; Raikar, S. B.; Wypych, J.-C.; Delpech, B.; Marazano, C. J. Org. Chem. 2009, 74, 9413. (b) Chang, J.-K.; Chang, B.-R.; Chuang, Y.-H.; Chang, N.-C. Tetrahedron 2008, 64, 41, 9685.

S15

N

HO

H

H

H

MeOOMe

(+)-11b-epi-Protoemetinol 11b-α-trans-12: The title compound was prepared from 11b-α-trans-11b in 78 % yield according to the general procedure B described above. [α]20

D = 43 (CDCl3, c = 0.006). All characterization data was in accordance with those previously reported.5

N

HO

H

H

H

MeOOMe

(+)-3-epi-11b-epi-Protoemetinol 11b-β-cis-12: The title compound was prepared from 11b-β-cis-11b in 91 % yield according to the general procedure A described above. 1H NMR (500 MHz, CDCl3): ™ 6.62 (s, 1H), 6.55 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.79 (dt, J = 10.3, 6.8 Hz, 1H), 3.71 (dt, J = 10.3, 7.32 Hz, 1H), 3.25 (broad d, J = 11.6 Hz, 1H), 3.09 (ddd, J = 15.4, 11.9, 6.4 Hz, 1H), 2.93 (dd, J = 11.3, 5.8 Hz, 1H), 2.71 (dd, J = 11.6, 3.5 Hz, 1H), 2.60 (dd, J = 15.9, 2.6 Hz, 1H), 2.50 (td, J = 11.3, 3.8 Hz, 1H), 2.24 (dt, J = 13.4, 2.5 Hz, 1H), 2.19 (t, J = 11.7 Hz, 1H), 2.00 (m, 1H), 1.84 (m, 1H), 1.63 (overlapping peaks, 2H), 1.58 (td, J = 12.3, 4.2 Hz, 1H), 1.26 (q, J = 7.2 Hz, 1H), 1.25 (q, J = 7.2 Hz, 1H), 0.91 (t, J = 7.4 Hz, 1H). 13C-NMR: (125 MHz, CDCl3): δ 147.4, 147.1, 130.2, 127.1, 111.6, 108.2, 61.9, 57.3, 57.1, 56.1, 55.8, 52.6, 40.9, 35.1, 32.2, 29.1, 28.5, 23.6, 11.7. MS (APCI): m/z (%): 320.1 (100) [M+H]+. [α]20

D = 100 (CDCl3, c = 0.03).

N

HO

H

H H

S

Compound 10b-α-trans-13: The title compound was prepared from 10b-α-trans-11c in 82 % yield according to the general procedure A described above. 1H NMR (500 MHz, CDCl3): δ 7.06 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 3.77-3.65 (m, 2H), 3.11 (m, 1H), 3.05 (dd, J = 8.8, 3.1 Hz, 1H), 3.02 (dd, J = 6.2, 5.5 Hz, 1H), 2.98 (broad d, J = 11.6 Hz, 1H), 2.76 (dd, J = 16.2, 4.4 Hz, 1H), 2.55 (ddd, J = 11.4, 11,3. 4.2 Hz, 1H), 2.24 (ddd, J = 12.7, 2.8, 2.7 Hz, 1H), 2.02 (dd, J = 11.0, 10.8 Hz, 1H), 1.92 (ddd, J = 11.5, 8.0, 7.5 Hz, 1H), 1.78 (broad s, 1H), 1.66 (m, 1H), 1.46-1.33 (m, 3H), 1.20 (ddd, J = 11.6, 11.4, 11.3 Hz, 1H), 1.12 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H) ppm. 13C-NMR: (125 MHz, CDCl3): δ 137.7, 133.8, 124.1, 122.8, 62.0, 60.6, 53.0, 41.9, 37.3, 37.1, 35.9, 25.7, 23.7, 11.2 ppm. MS (APCI): m/z (%): 266.1 (100) [M+H]+. [α]20

D = 11.1 (CDCl3, c = 0.025).

5 Takano, S.; Hatakeyama, S.; Takahashi, Y.; Ogasawara, K. Heterocycles 1982, 17, 263.

S16

N

HO

H

H H

S

Compound 10b-β-trans-13: The title compound was prepared from 10b-β-trans-11c in 68 % yield according to the general procedure B described above. 1H NMR (500 MHz, CDCl3): ™ 7.17 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 5.2 Hz, 1H), 3.87-3.80 (overlapping peaks, 2H), 3.62 (m, 1H), 3.12-3.08 (overlapping peaks, 2H), 2.86 (m, 1H), 2.78 (dd, J = 15.7, 4.13 Hz, 1H), 2.73 (dd, J = 11.6, 3.3 Hz, 1H), 2.64 (dd, J = 11.6, 5.2 Hz, 1H), 2.07 (ddd, J = 13.4, 8.9, 4.1 Hz, 1H), 1.96-1.85 (overlapping peaks, 3H), 1.72 (m, 1H), 1.69 (m, 1H), 1.62 (m, 1H), 1.58 (m, 1H), 1.44 (m, 1H), 0.98 (t, J = 7.5 Hz, 3H). 13C-NMR: (125 MHz, CDCl3): δ 134.6, 131.4, 121.8, 120.2, 59.0, 54.5, 50.2, 38.7, 33.4, 30.4, 30.2, 27.4, 22.8, 9.8. MS (APCI): m/z (%): 266.1 (100) [M+H]+. [α]20

D = 60.0 (CDCl3, c = 0.05). General procedure for partial reduction of quinolizidine hydrazones (Shapiro reaction):

N

AcO NNHTs

N

HO

n-BuLi

THF, 0 oC-rt.

Ar Ar

H

H H

HH H

The hydrazone compound 11 was dissolved in anhydrous THF (c = 0.1 M) under nitrogen atmosphere and cooled down to -78 °C. n-BuLi (5 equiv. 2.3 M in hexane) was added dropwise to this solution. During the addition the reaction mixture turned from yellow to brown and resulting solution was allowed to slowly reach room temperature and stirred overnight. Brine (5 mL) was added to quench the reaction and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH).

NH

HNH

HO

H

(-)-Corynantheol 12b-α-trans-16: The title compound was prepared from 11b-α-trans-11a in 67 % yield according to the general procedure described above. [α]20

D = -65.0 (CDCl3, c = 0.05) (Lit: [α]20D = -61). All characterization data was in

accordance with those previously reported.6

NH

H

MeOOMe

HO

H

Dehydroprotoemetinol 11b-α-trans-17: The title compound was prepared from 11b-α-trans-11b in 62 % yield according to the general procedure described 6 Massiot, G.; Thepenier, P.; Jacquier, M. J., Le Men-Olivier, L.; Verpoorte, R.;Delaude, C.

Phytochemistry 1987, 26, 2839.

S17

above. 1H NMR (500 MHz, CDCl3): ™ 6.67 (s, 1H), 6.58 (s, 1H), 5.56 (ddd, J = 19.0 Hz, 10.0 Hz, 9.5 Hz, 1H), 5.36 (br s, 1H), 5.16 (dd, J = 17.5, 1.0 Hz, 1H), 5.13 (dd, J = 6.5, 1.5 Hz, 1H), 3.88-3.86 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78-3.72 (m, 2H), 3.43 (br d, J = 11.0 Hz, 1H), 3.21-3.07 (m, 3H), 2.75-2.71 (m, 1H), 2.65 (td, J = 11.0, 5.0 Hz, 1H), 2.40 (t, J = 12.0 Hz, 1H), 2.40-2.36 (m, 1H), 2.32-2.25 (m, 1H), 1.83-1.87 (m, 1H), 1.66-1.60 (m, 1H), 1.42-1.36 (m, 2H).

NH

H

MeOOMe

HO

H

11b-epi-Dehydroprotoemetinol 11b-β-trans-17: The title compound was prepared from 11b-β-trans-11b in 65 % yield according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 6.70 (s, 1H), 6.57 (s, 1H), 5.77 (ddd, J = 18.0 Hz, 9.5 Hz, 9.5 Hz, 1H), 5.08 (dd, J = 17.0 Hz, 1.0 Hz, 1H), 5.00 (dd, J = 10.0 Hz, 1.5 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.80-3.72 (m, 2H), 3.09-2.94 (m, 3H), 2.64-2.57 (m, 2H), 2.49 (dd, J = 15.0 Hz, 5.0 Hz, 1H), 2.28 (dm, J = 13.0 Hz, 1H), 2.17-2.11 (m, 1H), 1.87-1.81 (m, 1H), 1.77 (ddd, J = 13.5 Hz, 8.0 Hz, 3.5 Hz, 1 H), 1.57-1.50 (m, 3H). 13C NMR (125 MHz, CDCl3): ™ 147.5, 147.4, 141.1, 128.8, 127.0, 115.5, 111.9, 108.5, 61.1, 56.7, 56.0, 55.9, 53.1, 51.7, 45.8, 36.0, 32.8, 32.5, 30.4.

NH

H

S

HO

H

Compound 10b-α-trans-18: The title compound was prepared from 10b-α-trans-11c in 43% yield according to the general procedure described above. 1H-NMR (400 MHz, CDCl3): 7.08 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 5.58 (ddd, J = 18.5, 10.0, 8.7 Hz, 1H), 5.15 (ddd, J = 18.5, 10.0, 1.4 Hz, 1H), 5.11 (d, J = 10.3 Hz, 1H), 3.80-3.67 (m, 2H), 3.28-3.01 (m, 3H), 2.96 (m, 1H), 2.81 (dd, J = 16.0, 3.1 Hz, 1H), 2.67 (m, 1H), 2.45-2.22 (m, 3H), 1.90 (dddd, J = 13.9, 7.8, 7.6, 3.3 Hz, 1H), 1.57 (m, 1H), 1.46-1.20 (m, 3H) ppm. 13C-NMR: (125 MHz, CDCl3): δ 139.1, 133.5, 123.9, 123.2, 117.6, 107.8, 62.0, 60.8, 60.4, 52.5, 46.4, 36.9, 36.4, 30.9, 29.7. MS (APCI): m/z (%): 264 (100) [M+H]+. [α]20

D = +1.8 (CDCl3, c = 0.003). General procedure for the oxidation of hydroxy-quinolizidine derivatives:

N

HO

N

O

Dess Martinperiodinane

DCM, r.t.

Ar Ar

H

H H

H

H H

To a solution of the corresponding substrate in DCM (0.1 M) was added Dess-Martin periodinane (1.1 equiv.) at room temperature and the reaction was stirred for 2 h. NaOH (5% aq., 10 drops) was added to quench the reaction. The mixture was stirred for 30 min at room temperature before it was diluted with water. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried

S18

(Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH).

NH

HNH

O

H

(-)-Dihydrocorynantheal 12b-α-trans-19: The title compound was prepared from 12b-α-trans-15 in 78% yield according to the general procedure described above. [α]20

D = -41.0 (CDCl3, c = 0.003) (Lit: [α]20D = -103 (Pyridine, c = 1.00)). All

characterization data was in accordance with those previously reported.7

NH

HNH

O

H

(-)-Corynantheal 12b-α-trans-20: The title compound was prepared from 11b-α-trans-16 in 82 % yield according to the general procedure described above. [α]20

D = -40.0 (CDCl3, c = 0.002) (Lit: [α]20D = -48.5). All characterization data was

in accordance with those previously reported.7,8

NH

H

MeOOMe

O

H

(-)-Protoemetine 11b-α-trans-21: The title compound was prepared from 11b-α-trans-12 in 92 % yield according to the general procedure described above. [α]20

D = -14.2 (EtOH, c = 0.007) (Lit: [α]28D = -14.4 (EtOH, c = 0.57)). All

characterization data was in accordance with those previously reported.2

NH

H

MeOOMe

O

H

11b-epi-Dehydroprotoemetine 11b-β-trans-22: The title compound was prepared from 11b-β-trans-17 in 90 % yield according to the general procedure described above. 1H NMR (500 MHz, CDCl3): ™ 9.81 (br s, 1H), 6.83 (s, 1H), 6.58 (s, 1H), 5.59 (ddd, J = 18.0, 9.5, 9.5 Hz, 1H), 5.09 (dd, J = 17.0 1.5 Hz, 1H), 5.04 (dd, J = 10.0, 1.5 Hz, 1H), 3.98 (br m, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.13-3.08 (m, 2H), 3.03 (td, J = 12.0, 7.0 Hz, 1H), 2.70 (dd, J = 18.0, 4.0 Hz, 1H), 2.60 (d, J = 7.0 Hz, 2H), 2.48 (dd, J = 16.5, 2.5 Hz, 1H), 2.43 (dt, J = 14.0, 4.0 Hz, 1H), 2.35 (ddd, J = 18.0, 10.0, 0.5 Hz, 1H), 2.12 (m, 1H), 1.97-1.91 (m, 1H), 1.67 (ddd, J = 13.5, 10.0, 4.0 Hz, 1H).

7 a) Kametani, T.; Kanaya, N.; Hino, H.; H.; S.-P.; Ihara, M. J. Chem. Soc., Perkin Trans 1, 1981,

3168. b) Bulletin de la Societe Chimique de France, 1953, 1033-1037 c) Helvetica Chimica Acta 1955, 38, 1073,1077

8 Jarreau, F.-X.; Goutare, R.; Djakoure, A. Tetrahedron, 1975, 31, 2247.

S19

N

O

H

H H

S

Compound 10b-α-trans-23: The title compound was prepared from 10b-α-trans-13 in 78 % yield according to the general procedure described above. 1H-NMR (500 MHz, CDCl3): ™ 9.86 (t, J = 1.8 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.76 (d, J = 5.3 Hz, 1H), 3.11-3.02 (overlapping peaks, 3H), 2.77 (dd, J = 15.7, 4.7 Hz, 1H), 2.70 (dd, J = 16.8, 3.3 Hz, 1H), 2.58 (td, J = 11.3, 3.9 Hz, 1H), 2.29 (ddd, J = 16.9, 8.6, 2.4 Hz, 1H), 2.25 (ddd, J = 13.3, 4.1, 2.7 Hz, 1H), 2.07 (t, J = 11.2 Hz, 1H), 1.92 (m, 1H), 1.57 (m, 1H), 1.47 (m, 1H), 1.27 (apparent q, J = 11.4, 1H), 1.25 (m, 1H), 1.13 (m, 1H), 0.92 (t, J = 7.5, 3H). 13C NMR (MHz, CDCl3): 202.4, 137.2, 133.7, 61.7, 60.1, 53.0, 52.9, 48.0, 41.7, 37.9, 35.6, 25.6, 23.7, 11.1. ™ MS (APCI): m/z (%): [M+H]+. [α]20

D = -15.7 (CDCl3, c = 0.008).

NH

HO

H

HO

H

HN

15

Preparation of (-)-(15S)-Hydroxydihydrocorynantheol 12b-α-trans-24. The crude ketone 12b-α-trans-9a, prepared according to the general procedure, was co-evaporated two times from toluene to remove all pyridine from the crude mixture and then dissolved in THF (0.1 M). The solution was cooled to -78 °C and L-Selectride (5 equiv., 1M in THF) was added dropwise. The mixture was stirred for 30 minutes at -78°C before HCl(aq) (2 M) was added. The water phase was extracted with ether before being basified with Na2CO3(aq) (2 M). The basic water phase was extracted with DCM and the combined DCM phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by FC (EtOAc/MeOH) to give an inseparatable mixture of (15S)-Hydroxydihydrocorynantheol 12b-α-trans-24 and (15R)-Hydroxydihydrocorynantheol 12b-α-trans-24, d.r. 77/23, in 89 % combined yield and 50 % overall combined yield from amide 2a. All characterization data was in accordance with those previously reported.9 Purification free multi-gram preparation of quinolizidine hydrazones. Compound 12b-α-trans-11a.

O

HO

11.20 g

12 mmol

12β−α-trans-11a2a2.44 g

10 mmol

2.77 g53 % overall yield

HNO

O

NH

N

NNHTs

H

HNH

AcO

H

β-Ketoamide 2a (2.44 g, 10 mmol) and (R)-catalyst 3 (650 mg, 2 mmol) was dissolved in DCM (10 mL). To this solution was added 5-hydroxyl-pentaldehyde 1 (1.20 g, 1.2 mmol) and the resulting reaction mixture was stirred until a white or 9 Weiniger, B.; Anton, R. Journal of Natural Products, 1994, 57, 287.

S20

white/brown precipitate was formed that indicates full conversion. Acetyl chloride (100 mmol, 7.10 ml) was added and the mixture was stirred O.N. at room temperature. The reaction was quenched by addition of saturated NaHCO3 (aq.) and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) followed by addition of di-tert-butylpyridine (5.70 g, 35 mmol) and Et3O.BF4 (3.80 g, 25 mmol). After 4 h was DCM removed under vacuum and the residue re-dissolved in methanol (150 mL) and cold to 0 oC. NaBH4 (2.30 g, 60 mmol) was added in small portions and the resulting mixture was stirred for 1 hour at room temperature. Methanol was removed under vacuum and the residue was dissolved in THF (100 ml) and 2 M HCl (aq.) (100 mL). The mixture was stirred O.N. before being quenched with sat. NaHCO3 and NaOH (10 mL, 5 % aqueous solution). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4). DCM was removed under vacuum until approx. 100 mL remained. Pyridine (8.0 g, 100 mmol), DMAP (30 mg, 0.2 mmol) and acetic anhydride (10 g, 100 mmol) were added to this solution in turn. The reaction was left for 4 h at room temperature before sat. NaHCO3 was added. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4). The solvent was removed and the residue was dissolved in methanol (120 mL) and acetic acid (40 mL) followed by addition of tosylhydrazide (3.72 g, 20 mmol). The reaction was stirred overnight at room temperature before being quenched with sat. NaHCO3. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified with column chromatography to give 12b-α-trans-11a as a yellow solid. (2.77 g, overall yield: 53 %). Compound 11b-α-trans-11b / 11b-β-cis-11b.

O

HNO

O

HO

11.20 g

12 mmol

OMe

OMe

N

AcO

H

NNHTs

N

AcO

H

NNHTs

MeOOMe

MeOOMe

HH H H

11b-α-trans-9b 11b-β-cis-9b22.65 g

10 mmol3.38 g

62 % overallcombinde yield

d.r. 1:1 β-Ketoamide 2b (2.65 g, 10 mmol) and (R)-catalyst 3 (650 mg, 2 mmol) was dissolved in DCM (10 mL). To this solution was added 5-hydroxyl-pentaldehyde 1 (1.20 g, 1.2 mmol) and the resulting reaction mixture was stirred until a white or white/brown precipitate was formed that indicates full conversion. Triflouro acetic acid (10 ml) was added and the mixture was stirred for one additional hour at room temperature. The reaction was quenched by addition of saturated NaHCO3 (aq.) and the water phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) followed by addition of di-tert-butylpyridine (5.70 g, 35 mmol) and Et3O.BF4 (3.80 g, 25 mmol). After 4 h was DCM removed under vacuum and the residue re-dissolved in methanol (150 mL) and cold to 0 oC. NaBH4 (2.30 g, 60 mmol) was added in small portions and the resulting mixture was stirred for 1 hour at room temperature. The methanol was removed under vacuum and the residue was

S21

dissolved in THF (100 ml), cooled to 0 °C followed by addition of a pre-cold solution of 2 M HCl (aq.) (100 mL). The mixture was stirred for 2 h before being quenched with sat. NaHCO3 and NaOH (10 mL, 5 % aqueous solution). The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4). DCM was removed under vacuum until approx. 100 mL remained. Pyridine (8.0 g, 100 mmol), DMAP (30 mg, 0.2 mmol) and acetic anhydride (10 g, 100 mmol) were added to this solution in turn. The reaction was left for 4 h at room temperature before sat. NaHCO3 was added. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4). The solvent was removed and the residue was dissolved in methanol (120 mL) and acetic acid (40 mL) followed by addition of tosylhydrazide (3.72 g, 20 mmol). The reaction was stirred overnight at room temperature before being quenched with sat. NaHCO3. The water phase was extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified with column chromatography to give a 1:1 mixture of α-trans-11b and β-cis-11b as yellow solid (3.38 g, overall combined yield: 62%). (Precaution: α-trans-11b and β-cis-11b was inseparatable by FC.)

S22

Optimization of Acid Conditions for the N-Acyliminium ion Cyclization: Table S1: Optimization of acid conditions for indolo[2,3-a]quinolizidine.[a]

N

O

O

HN

N

O

H

β-7a(Kinetic)

Oα-7a

(Thermodynamic)

O

HNO

O NH OTMS

PhPh

1)

2) Acid conditions

HO

1 2a

DCM

HH

HHN

NH

Entry Acid. Equiv. T (oC) t (h) dr [12b-α-7a

/12b-β-7a] [b] 1 HCl 0.4 -78→r.t 16 1/1.5 2 TFA excess -20 5 1/1.1 3 TFA excess reflux 1 4/1 4 TFA excess reflux O.N. 4/1 5 HCO2H excess r.t. 4h 1/1.6 6 HCO2H excess -20 48 1/1.7 7 AcOH excess r.t. O.N. complex mix. 8 TsOH 0.2 r.t. O.N. 1/1.2 9 H3PO4 excess r.t. 5 6.2/1 10 AcCl 10 r.t. O.N. >10/1 11 AcCl 0.4 r.t. O.N. 1/1.5 12 AcCl 1 -78→r.t O.N. 1/2.1 13 AcCl/Et3N 1 -78→r.t O.N. 1/2.1 14 BzCl excess r.t O.N. 1/1.4 15 BzCl 1.2 -78→r.t O.N. 1/4 16 BzCl 1.2 r.t 16 1/1.5 17 Pivaloyl chloride 1.2 r.t 16 2.7/1 18 (Et)3O.BF4 3 -78→r.t O.N. 1/1 19 Ac2O excess r.t. O.N. complex mix 20 (CF3CO)2O 3 -78→r.t O.N. 1/2.3 21 (CF3CO)2O 0.5 -78→r.t O.N. 1/1.7 22 BF3OEt2 excess -78→r.t O.N. Decomposition 23 SnCl4 2 r.t. 5 1/1 24 Sm(OTf)3 10 r.t. O.N. trace 25 FeCl3 10 r.t. O.N. 1/1 [a] A solution of aldehyde 1 (1.2 equiv), amide 2a (1 equiv) and catalyst 3 (20 mol%) in DCM (1 M) was stirred at room temperature. After full conversion of 2a, the given acid was added to the reaction mixture at the given temperature. [b] Determined by 1H NMR spectroscopy on the crude reaction mixture.

S23

Table S1: Optimization of acid conditions for benzo[a]quinolizidines.[a]

N

O

O

N

O

H

β-7b(Kinetic)

Oα-7b

(Thermodynamic)

O

HNO

O NH OTMS

PhPh

1)

2) Acid conditions

HO

1 2b

DCMHH

H

OMeMeO

MeOOMe OMe

MeO

Entry Acid. Equiv. T (oC) t (h) dr [11b-α-7b

/11b-β-7b] [b] 1 TFA Excess -20 O.N. 1/1.2 2 TFA Excess reflux 1 1.7/1 3 TFA Excess reflux O.N. 1.8/1 4 HCO2H 1.5 r.t. 4h 1.8/1 5 HCl 1.5 -78→r.t O.N. 1/1.8 6 AcOH Excess 60 O.N. Complex mix. 7 Ac2O Excess r.t O.N. No cyclization 8 (CF3CO)2O 3 -78→r.t O.N. No cyclization 9 TsOH 0.2 r.t. O.N. No cyclization 10 AcCl 10 -78→r.t O.N. 1/1 11 MsCl Excess r.t. O.N. No cyclization 12 TMSOTf 2 r.t O.N. 1/4.0 13 (Et)3OBF4 3 -78→r.t O.N. 2.3/1 14 (Et)3OBF4 1.2 -78→r.t O.N. Complex mix. 15 (Et)3OBF4 1.2 r.t O.N. 2/1 16 SnCl4 1.5 r.t 5 1/4 17 TiCl4 13 r.t 16 1/2 18 AlCl3 5 r.t 16 1/1.8 A solution of aldehyde 1 (1.2 equiv), amide 2b (1 equiv) and catalyst 3 (20 mol%) in DCM (1 M) was stirred at room temperature. After full conversion of 2b, the given acid was added to the reaction mixture at the given temperature. [b] Determined by 1H NMR spectroscopy on the crude reaction mixture.

S24

Table S1: Optimization of acid conditions for thieno[3,2-a]quinolizidine.[a]

N

O

O

N

O

H

β-7c(Kinetic)

Oα-7c

(Thermodynamic)

O

HNO

O NH OTMS

PhPh

1)

2) Acid conditions

HO

1 2c

DCM HH

H

S S S

Entry Acid. Equiv. T (oC) t (h) dr [10b-α-7c

/10b-β-7c] [b] 1 HCl 0.4 -78→r.t O.N. 35:65 2 TFA Excess r.t. 4 57:43 3 TFA Excess reflux 1 63:37 4 TFA Excess reflux 4 63:37 5 AcOH Excess r.t. 12 No conversion 6 H3PO4 Excess r.t. 12 42:58 7 TfOH 0.6 r.t. 12 57:43 8 TMSOTf 2 r.t. 12 41:59 9 SnCl4 5 r.t. 12 33:67 10 Et3OBF4 3 r.t. 12 67:33 11 BF3Et2O Excess r.t. 12 Complex mix. 12 Benzoyl chloride 1.2 -78→r.t 12 36:64 13 Benzoyl chloride Excess r.t 12 33:67 14 AcCl 10 -78→r.t 12 42:58 15 AcCl 10 r.t 12 40:60 A solution of aldehyde 1 (1.2 equiv), amide 2c (1 equiv) and catalyst 3 (20 mol%) in DCM (1 M) was stirred at room temperature. After full conversion of 2c, the given acid was added to the reaction mixture at the given temperature. [b] Determined by 1H NMR spectroscopy on the crude reaction mixture.

S25

Compound 2a

HN

O OHN

HN

O OHN

S26

Compound 2b

HN

O O

MeO

MeO

HN

O O

MeO

MeO

S27

Compound 2c

HN

O OS

HN

O OS

S28

Compound 12b-α-7a

N

O

O

H

H

HN

N

O

O

H

H

HN

S29

Compound 12b-β-7a

N

O

O

H

H

HN

N

O

O

H

H

HN

S30

Compound 11b-α-7b

N

O

O

OO

H

H

N

O

O

OO

H

H

S31

Compound 11b-β-7b

N

O

O

OO

H

H

N

O

O

OO

H

H

S32

Compound 10b-α-7c

N

O

O

H

H

S

N

O

O

H

H

S

S33

Compound 10b-β-7c

N

O

O

H

H

S

N

O

O

H

H

S

S34

Compound 12b-α-8a

N

O

H

HNH

N

O

H

HNH

S35

Compound 12b-β-8a

N

O

H

HNH

N

O

H

HNH

S36

Compound 11b-α-8b

N

O

H

H

MeOOMe

N

O

H

H

MeOOMe

S37

Compound 11b-β-8b

N

O

H

H

MeOOMe

N

O

H

H

MeOOMe

S38

Compound 10b-α-8c

N

O

H

S

H

N

O

H

S

H

S39

Compound 10b-β-8c

N

O

H

S

H

N

O

H

S

H

S40

Compound 12b-α-trans-11a

N

NNHTs

H

HNH

AcO

H

N

NNHTs

H

HNH

AcO

H

S41

Compound 12b-β-trans-11a

N

NNHTs

H

HNH

AcO

H

N

NNHTs

H

HNH

AcO

H

S42

Compound 12b-β-cis-11a

N

NNHTs

H

HNH

AcO

H

N

NNHTs

H

HNH

AcO

H

S43

Compound 11b-α-trans-11b

N

NNHTs

H

H

MeOOMe

AcO

H

N

NNHTs

H

H

MeOOMe

AcO

H

S44

Compound 11b-β-trans-11b

N

NNHTs

H

H

MeOOMe

AcO

H

N

NNHTs

H

H

MeOOMe

AcO

H

S45

Compound 11b-β-cis-11b

N

NNHTs

H

H

MeOOMe

AcO

H

N

NNHTs

H

H

MeOOMe

AcO

H

S46

Compound 10b-α-trans-11c

N

NNHTs

H

H

S

AcO

H

N

NNHTs

H

H

S

AcO

H

S47

Compound 10b-β-trans-11c

N

NNHTs

H

H

S

AcO

H

N

NNHTs

H

H

S

AcO

H

S48

Compound 10b-β-cis-11c

N

NNHTs

H

H

S

AcO

H

N

NNHTs

H

H

S

AcO

H

S49

(+)-Hirsutinol 12b-β-trans-15:

N

HO

H

H H

HN

N

HO

H

H H

HN

S50

(+)-3-epi-Hirsutinol 12b-β-cis-15:

N

HO

H

H H

HN

S51

(+)-3-epi-11b-epi-Protoemetinol 11b-β-cis-12

N

HO

H

H

H

MeOOMe

N

HO

H

H

H

MeOOMe

S52

Compound 10b-α-trans-13

N

HO

H

H H

S

N

HO

H

H H

S

S53

Compound 10b-β-trans-13

N

HO

H

H H

S

N

HO

H

H H

S

S54

Compound 11b-α-trans-17

NH

H

MeOOMe

HO

H

S55

Compound 11b-β-trans-17

NH

H

MeOOMe

HO

H

NH

H

MeOOMe

HO

H

S56

Compound 10b-α-trans-18

NH

H

S

HO

H

NH

H

S

HO

H

S57

Compound 11b-β-trans-22

NH

H

MeOOMe

O

H

S58

Compound 10b-α-trans-23

N

O

H

H H

S

N

O

H

H H

S